Protein:SRC |
Protein Summary |
 Gene summary |
| Gene name: SRC | ASpdb.0 ID: 6714 | Gene | Gene symbol | SRC | Gene ID | 6714 |
| Gene name | SRC proto-oncogene, non-receptor tyrosine kinase |
| Synonyms | ASV|SRC1|THC6|c-SRC|p60-Src |
| Cytomap | 20q11.23 |
| Type of gene | protein-coding |
| Description | proto-oncogene tyrosine-protein kinase Srcproto-oncogene c-Srcprotooncogene SRC, Rous sarcomatyrosine kinase pp60c-srctyrosine-protein kinase SRC-1v-src avian sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog |
| Modification date | 20240411 |
| UniProtAcc | P12931 |
| Gene ontology of this gene with evidence of Inferred from Direct Assay (IDA) from Entrez |
| Partner | Gene | GO ID | GO term | PubMed ID |
| Gene | SRC | GO:0004672 | protein kinase activity | 18616680 |
| Gene | SRC | GO:0004713 | protein tyrosine kinase activity | 16441665|19059439|19307596|35927303 |
| Gene | SRC | GO:0004715 | non-membrane spanning protein tyrosine kinase activity | 11606584|33963050 |
| Gene | SRC | GO:0005654 | nucleoplasm | - |
| Gene | SRC | GO:0005737 | cytoplasm | 16441665 |
| Gene | SRC | GO:0005739 | mitochondrion | 19767770 |
| Gene | SRC | GO:0005743 | mitochondrial inner membrane | 12615910 |
| Gene | SRC | GO:0005764 | lysosome | 20605918 |
| Gene | SRC | GO:0005770 | late endosome | 20605918 |
| Gene | SRC | GO:0005829 | cytosol | 19767770 |
| Gene | SRC | GO:0005886 | plasma membrane | 20605918 |
| Gene | SRC | GO:0005901 | caveola | 17848177 |
| Gene | SRC | GO:0016004 | phospholipase activator activity | 11606584 |
| Gene | SRC | GO:0018108 | peptidyl-tyrosine phosphorylation | 22732588 |
| Gene | SRC | GO:0018108 | peptidyl-tyrosine phosphorylation | 12051764 |
| Gene | SRC | GO:0020037 | heme binding | 21036157 |
| Gene | SRC | GO:0030054 | cell junction | - |
| Gene | SRC | GO:0034139 | regulation of toll-like receptor 3 signaling pathway | 37158982 |
| Gene | SRC | GO:0035306 | positive regulation of dephosphorylation | 23159740 |
| Gene | SRC | GO:0035556 | intracellular signal transduction | 11606584|15248232 |
| Gene | SRC | GO:0045747 | positive regulation of Notch signaling pathway | 25731159 |
| Gene | SRC | GO:0046777 | protein autophosphorylation | 16441665 |
| Gene | SRC | GO:0048471 | perinuclear region of cytoplasm | 19307596 |
| Gene | SRC | GO:0060576 | intestinal epithelial cell development | 25731159 |
| Gene | SRC | GO:0070102 | interleukin-6-mediated signaling pathway | 25731159 |
| Gene | SRC | GO:0071902 | positive regulation of protein serine/threonine kinase activity | 19059439 |
| Gene | SRC | GO:1904263 | positive regulation of TORC1 signaling | 35927303 |
AS Summary |
| Information of the canonical protein with experimentally identified structure from PDB (2023). |
| UniProt Acc | File name | PDB ID | Method | Resolution | Chain | Start | End |
| P12931-1 | P12931-1_1fmk_A.pdb | 1FMK | X-ray | 1.5 | A | 86 | 536 |
| ASpdb's canonical and alternatively spliced isoform information. |
| accession_id | gene_name | canonical_id | alternative_id | canonical_length | alternative_length | canonical_start | canonical_end | type | originalSEQ | variationSEQ | alternative_start | alternative_end |
| P12931 | SRC | P12931-1 | P12931-2 | 536 | 542 | 117 | 117 | Substitution | T | TRKVDVR | 117 | 123 |
| Multiple sequence alignment of our canonical and alternatively spliced SRC |
| Matched gene isoform IDs with Ensembl and RefSeq of our canonical and alternative spliced genes of SRC |
| UniProt-id | ENSG | ENST | ENSP |
| P12931-1 | ENSG00000197122.13 | ENST00000373567.6 | ENSP00000362668.2 |
| P12931-1 | ENSG00000197122.13 | ENST00000373578.7 | ENSP00000362680.2 |
| P12931-1 | ENSG00000197122.13 | ENST00000692112.1 | ENSP00000508666.1 |
| P12931-1 | ENSG00000197122.13 | ENST00000692423.1 | ENSP00000509325.1 |
| P12931-1 | ENSG00000291971.1 | ENST00000709392.1 | ENSP00000517666.1 |
| P12931-1 | ENSG00000291971.1 | ENST00000709394.1 | ENSP00000517668.1 |
| P12931-1 | ENSG00000291971.1 | ENST00000709395.1 | ENSP00000517669.1 |
| P12931-1 | ENSG00000291971.1 | ENST00000709396.1 | ENSP00000517670.1 |
| P12931-2 | ENSG00000197122.13 | ENST00000373558.2 | ENSP00000362659.2 |
| P12931-2 | ENSG00000291971.1 | ENST00000709397.1 | ENSP00000517671.1 |
| UniProt-id | NM ID | NP ID |
| P12931-1 | NM_005417.4 | NP_005408.1 |
| P12931-1 | NM_198291.2 | NP_938033.1 |
| P12931-2 | XM_017028026.1 | XP_016883515.1 |
| Amino acid sequences of our canonical and alternatively spliced SRC |
| accession_id | Protein sequence |
| P12931-1 | MGSNKSKPKDASQRRRSLEPAENVHGAGGGAFPASQTPSKPASADGHRGPSAAFAPAAAEPKLFGGFNSSDTVTSPQRAGPLAGGVTTFV ALYDYESRTETDLSFKKGERLQIVNNTEGDWWLAHSLSTGQTGYIPSNYVAPSDSIQAEEWYFGKITRRESERLLLNAENPRGTFLVRES ETTKGAYCLSVSDFDNAKGLNVKHYKIRKLDSGGFYITSRTQFNSLQQLVAYYSKHADGLCHRLTTVCPTSKPQTQGLAKDAWEIPRESL RLEVKLGQGCFGEVWMGTWNGTTRVAIKTLKPGTMSPEAFLQEAQVMKKLRHEKLVQLYAVVSEEPIYIVTEYMSKGSLLDFLKGETGKY LRLPQLVDMAAQIASGMAYVERMNYVHRDLRAANILVGENLVCKVADFGLARLIEDNEYTARQGAKFPIKWTAPEAALYGRFTIKSDVWS |
| P12931-2 | MGSNKSKPKDASQRRRSLEPAENVHGAGGGAFPASQTPSKPASADGHRGPSAAFAPAAAEPKLFGGFNSSDTVTSPQRAGPLAGGVTTFV ALYDYESRTETDLSFKKGERLQIVNNTRKVDVREGDWWLAHSLSTGQTGYIPSNYVAPSDSIQAEEWYFGKITRRESERLLLNAENPRGT FLVRESETTKGAYCLSVSDFDNAKGLNVKHYKIRKLDSGGFYITSRTQFNSLQQLVAYYSKHADGLCHRLTTVCPTSKPQTQGLAKDAWE IPRESLRLEVKLGQGCFGEVWMGTWNGTTRVAIKTLKPGTMSPEAFLQEAQVMKKLRHEKLVQLYAVVSEEPIYIVTEYMSKGSLLDFLK GETGKYLRLPQLVDMAAQIASGMAYVERMNYVHRDLRAANILVGENLVCKVADFGLARLIEDNEYTARQGAKFPIKWTAPEAALYGRFTI KSDVWSFGILLTELTTKGRVPYPGMVNREVLDQVERGYRMPCPPECPESLHDLMCQCWRKEPEERPTFEYLQAFLEDYFTSTEPQYQPGE |
Protein Functional Features |
| Main function of this protein. (from UniProt) |
| SRC (go to UniProt):P12931 |
| Retention analysis result of protein across 39 protein features of UniProt such as six molecule processing features, 13 region features, four site features, six amino acid modification features, two natural variation features, five experimental info features, and 3 secondary structure features. Here, because of limited space for viewing, we only show the protein feature retention information belong to the 13 regional features. All retention annotation result can be downloaded at * Minus value of BPloci means that the break pointn is located before the CDS. |
| - Retained protein feature among the 13 regional features. |
| Accession_id | Subsection | Start | End | Funcitonal feature | Splicing information |
| P12931 | Domain | 84 | 145 | Note=SH3;Ontology_term=ECO:0000255;evidence=ECO:0000255|PROSITE-ProRule:PRU00192 | Type=Substitution;Start=117;End=117 |
Gene Isoform Structures and Expression Levels for SRC |
| Gene structures of our canonical and alternative spliced genes of SRC * Click on the image to open the UCSC genome browser with custom track showing this image in a new window. |
| Expression levels of gene isoforms across GTEx. |
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| Expression levels of gene isoforms across TCGA. |
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Protein Structures |
| PDB and CIF files of the predicted protein structures * Here we show the 3D structure of the proteins using Mol*. AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100. Model confidence is shown from the pLDDT values per residue. pLDDT corresponds to the model’s prediction of its score on the local Distance Difference Test. It is a measure of local accuracy (from AlphfaFold website). To color code individual residues, we transformed individual PDB files into CIF format. |
| 3D view using mol* of P12931-1 |
| 3D view using mol* of P12931-2 |
pLDDT Score Distribution |
| pLDDT score distribution of the predicted protein structures from AlphaFold2 * AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100. |
| pLDDT distribution across the protein length of P12931-1 |
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| pLDDT distribution across the protein length of P12931-2 |
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Ramachandran Plot of Protein Structures |
| Ramachandran plot of the torsional angles - phi (φ)and psi (ψ) - of the residues (amino acids) contained in this protein peptide. |
| Ramachandran plot of P12931-1 |
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| Ramachandran plot of P12931-2 |
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Potential Active Site Information |
| The potential binding sites of these proteins were identified using SiteMap, a module of the Schrodinger suite. |
| UniProt-id | Site score | Size | D score | Volume | Exposure | Enclosure | Contact | Phobic | Philic | Balance | Don/Acc | Residues |
| P12931-1 | 1.072 | 181 | 1.06 | 495.292 | 0.448 | 0.806 | 1.033 | 0.753 | 1.115 | 0.676 | 0.985 | 276,277,278,279,280,281,282,284,296,298,300,304,30 5,317,326,328,339,341,342,343,344,347,348,351,389, 391,393,394,396,406,407,408,410,411,414,419,426,42 8 |
| P12931-2 | 1.055 | 211 | 1.045 | 548.457 | 0.478 | 0.78 | 0.994 | 0.585 | 1.115 | 0.525 | 1.151 | 282,283,284,285,286,287,288,290,302,304,306,310,31 1,316,323,332,334,345,347,348,349,350,353,354,357, 395,397,399,400,402,412,413,414,416,417,420,425,43 1,432,433,434,435,436,437,477 |
Protein Structure and Feature Comparision |
| Protein Structure Comparision Using Template Modeling Scores (TM-score). |
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| Protein Structure Comparision Visualization with mol*. between Canonical predicted structure (AF2)(orange) vs Canonical validated structure (PDB)(green) |
| 3D view using mol* of P12931-1_P12931-1_1fmk_A.pdb |
| Protein Structure Comparision Visualization with mol*. between Canonical validated structure (PDB)(orange) vs Alternative predicted structure (AF2)(green) |
| 3D view using mol* of P12931-1_1fmk_A_P12931-2.pdb |
| Protein Structure Comparision Visualization with mol*. between Canonical predicted structure (AF2)(orange) vs Alternative predicted structure (AF2)(green) |
| 3D view using mol* of P12931-1_P12931-2.pdb |
| Protein Feature Comparison of the protein sequendary structures among the protiens. |
| ./stats/secondary_structure/figure/P12931-1_vs_P12931-2.png |
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| Protein Feature Comparison of the relative accessible surface area (ASA) among the protiens. |
| ./stats/relative_asa/P12931-1_vs_P12931-2.png |
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Protein-Protein Interaction |
| Interactors from UniProt. |
| Accession_id | Subsection | Start | End | Funcitonal feature | Splicing information |
| Interactors from STRING. |
| Gene name | Interactors |
Related Drugs to SRC |
| Drugs targeting this gene/protein. (DrugBank) |
| UniProt accession | Gene name | DrugBank ID | Drug name | Drug group | Actions |
| P12931 | SRC | DB04495 | Paratoulene phosphate | experimental | |
| P12931 | SRC | DB01866 | RU79256 | experimental | |
| P12931 | SRC | DB03023 | 1-Tert-Butyl-3-(4-Chloro-Phenyl)-1h-Pyrazolo[3,4-D]Pyrimidin-4-Ylamine | experimental | |
| P12931 | SRC | DB03525 | RU79073 | experimental | |
| P12931 | SRC | DB03114 | PAS219 | experimental | |
| P12931 | SRC | DB02762 | RU79072 | experimental | |
| P12931 | SRC | DB06882 | 1-[1-(3-aminophenyl)-3-tert-butyl-1H-pyrazol-5-yl]-3-naphthalen-1-ylurea | experimental | |
| P12931 | SRC | DB06616 | Bosutinib | approved | inhibitor |
| P12931 | SRC | DB08054 | 1-(1-methylethyl)-3-quinolin-6-yl-1H-pyrazolo[3,4-d]pyrimidin-4-amine | experimental | |
| P12931 | SRC | DB02908 | RU78783 | experimental | |
| P12931 | SRC | DB06883 | 1-[1-(3-aminophenyl)-3-tert-butyl-1H-pyrazol-5-yl]-3-phenylurea | experimental | |
| P12931 | SRC | DB07662 | PD-168393 | experimental | |
| P12931 | SRC | DB01678 | RU84687 | experimental | |
| P12931 | SRC | DB02432 | RU90395 | experimental | |
| P12931 | SRC | DB03078 | PASBN | experimental | |
| P12931 | SRC | DB09079 | Nintedanib | approved | inhibitor |
| P12931 | SRC | DB04272 | Citric acid | approved, nutraceutical, vet_approved | |
| P12931 | SRC | DB01908 | RU85493 | experimental | |
| P12931 | SRC | DB08564 | (2E)-N-{4-[(3-bromophenyl)amino]quinazolin-6-yl}-4-(dimethylamino)but-2-enamide | experimental | |
| P12931 | SRC | DB01893 | N6-Benzyl Adenosine-5'-Diphosphate | experimental | |
| P12931 | SRC | DB08462 | N-(4-PHENYLAMINO-QUINAZOLIN-6-YL)-ACRYLAMIDE | experimental | |
| P12931 | SRC | DB08053 | 1-cyclobutyl-3-(3,4-dimethoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine | experimental | |
| P12931 | SRC | DB03104 | 2-[4-[(Z)-2-Acetamido-3-oxo-3-[[(3S)-2-oxo-1-[(4-phenylphenyl)methyl]azepan-3-yl]amino]prop-1-enyl]-2-formylphenyl]acetic acid | experimental | |
| P12931 | SRC | DB08901 | Ponatinib | approved, investigational | inhibitor |
| P12931 | SRC | DB03217 | DPI59 | experimental | |
| P12931 | SRC | DB03828 | RU78299 | experimental | |
| P12931 | SRC | DB02336 | RU83876 | experimental | |
| P12931 | SRC | DB07966 | [4-({4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]quinazolin-2-yl}amino)phenyl]acetonitrile | experimental | |
| P12931 | SRC | DB03712 | RU85053 | experimental | |
| P12931 | SRC | DB04751 | Purvalanol A | experimental | |
| P12931 | SRC | DB01254 | Dasatinib | approved, investigational | inhibitor, multitarget |
| P12931 | SRC | DB03628 | ISO24 | experimental | |
| P12931 | SRC | DB08192 | 2-(4-CARCOXY-5-ISOPROPYLTHIAZOLYL)BENZOPIPERIDINE | experimental | |
| P12931 | SRC | DB01947 | RU78262 | experimental | |
| P12931 | SRC | DB08052 | PP-121 | experimental | |
| P12931 | SRC | DB06137 | Tirbanibulin | approved, investigational | inhibitor |
| P12931 | SRC | DB01962 | Phosphonotyrosine | experimental | |
| P12931 | SRC | DB03902 | Oxalic Acid | experimental | |
| P12931 | SRC | DB12010 | Fostamatinib | approved, investigational | inhibitor |
| P12931 | SRC | DB03268 | RU82197 | experimental | |
| P12931 | SRC | DB03298 | Phenylphosphate | experimental | |
| P12931 | SRC | DB04080 | RU78191 | experimental | |
| P12931 | SRC | DB07335 | 3-[4-AMINO-1-(1-METHYLETHYL)-1H-PYRAZOLO[3,4-D]PYRIMIDIN-3-YL]PHENOL | experimental | |
| P12931 | SRC | DB05184 | XL228 | investigational | |
| P12931 | SRC | DB03306 | RU78300 | experimental | |
| P12931 | SRC | DB02175 | Malonic acid | experimental | |
| P12931 | SRC | DB04739 | 4-[(4-METHYL-1-PIPERAZINYL)METHYL]-N-[3-[[4-(3-PYRIDINYL)-2-PYRIMIDINYL]AMINO]PHENYL]-BENZAMIDE | experimental | |
| P12931 | SRC | DB03591 | RU82209 | experimental |
Related Diseases to SRC |
| Previous studies relating to the alternative splicing of SRC and disease information from the MeSH term (PubMed) |
| Gene | PMID | Title | Abstract | MeSH ID | MeSH term |
| SRC | 11980671 | Focal adhesion kinase enhances signaling through the Shc/extracellular signal-regulated kinase pathway in anaplastic astrocytoma tumor biopsy samples. | Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that on activation generates signals that can modulate crucial cell functions, including cell proliferation, migration, and survival. In vitro, overexpression of FAK has been shown to promote cell proliferation by signaling through the Ras/mitogen-activated protein kinase cascade in several cell types. We have shown previously that overexpression of exogenous FAK lacking alternative splicing in malignant astrocytoma clones injected intracerebrally into SCID mouse brains promotes tumor cell proliferation. Here, we show that in anaplastic astrocytoma biopsy samples, FAK is expressed as an unspliced variant and migrates with a faster mobility similar to that observed in embryonic brain. Compared with nonneoplastic adult brain biopsies, the levels of FAK protein are elevated as are its levels of activation as assessed by autophosphorylation and overall tyrosine phosphorylation. The activity of Src kinase in these tumors is also elevated, as well as the activity of Src kinase associated with FAK; the latter may result in enhanced Src kinase phosphorylation of FAK. Phosphorylated Shc is associated with FAK in the anaplastic astrocytoma biopsy samples and in astrocytoma cells overexpressing FAK in vitro but not in nonneoplastic brain biopsy samples. Elevated extracellular signal-regulated kinase-2 activation and elevated expression of cyclins D and E are also found in anaplastic astrocytoma biopsy samples. These data provide evidence that the increased FAK activity in these tumors contributes to phosphorylation of Shc and likely to the promotion of Ras activity, extracellular signal-regulated kinase-2 activation, and cell proliferation in vivo. | D001254 | Astrocytoma |
| SRC | 11980671 | Focal adhesion kinase enhances signaling through the Shc/extracellular signal-regulated kinase pathway in anaplastic astrocytoma tumor biopsy samples. | Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that on activation generates signals that can modulate crucial cell functions, including cell proliferation, migration, and survival. In vitro, overexpression of FAK has been shown to promote cell proliferation by signaling through the Ras/mitogen-activated protein kinase cascade in several cell types. We have shown previously that overexpression of exogenous FAK lacking alternative splicing in malignant astrocytoma clones injected intracerebrally into SCID mouse brains promotes tumor cell proliferation. Here, we show that in anaplastic astrocytoma biopsy samples, FAK is expressed as an unspliced variant and migrates with a faster mobility similar to that observed in embryonic brain. Compared with nonneoplastic adult brain biopsies, the levels of FAK protein are elevated as are its levels of activation as assessed by autophosphorylation and overall tyrosine phosphorylation. The activity of Src kinase in these tumors is also elevated, as well as the activity of Src kinase associated with FAK; the latter may result in enhanced Src kinase phosphorylation of FAK. Phosphorylated Shc is associated with FAK in the anaplastic astrocytoma biopsy samples and in astrocytoma cells overexpressing FAK in vitro but not in nonneoplastic brain biopsy samples. Elevated extracellular signal-regulated kinase-2 activation and elevated expression of cyclins D and E are also found in anaplastic astrocytoma biopsy samples. These data provide evidence that the increased FAK activity in these tumors contributes to phosphorylation of Shc and likely to the promotion of Ras activity, extracellular signal-regulated kinase-2 activation, and cell proliferation in vivo. | D001932 | Brain Neoplasms |
| SRC | 17471235 | CD99 isoforms dictate opposite functions in tumour malignancy and metastases by activating or repressing c-Src kinase activity. | CD99 gene encodes two distinct proteins, produced by alternative splicing of CD99 gene transcript. Full-length CD99 isoform (CD99wt) is formed by an extracellular domain, followed by a transmembrane domain and a 36 amino-acid intracytoplasmic domain, which is partially deleted in the truncated, short form (CD99sh). A differential expression of these two CD99 molecules can lead to distinct functional outcomes in lymphocytes. To investigate the functional effects of CD99 molecules on malignancy, forced overexpression of the two CD99 isoforms was induced in osteosarcoma and prostate cancer cells. The two isoforms exhibited opposite functions: the major form dramatically inhibits anchorage-independent growth, anoikis resistance, migration and metastasis, whereas the CD99sh remarkably favours the phenomena. A mechanistic analysis of CD99-transfected osteosarcoma cells points to involvement of c-Src family kinase activity in regulating CD99 functions in malignancy. Ser168 residue of CD99 plays a pivotal role in the reversion of the malignant phenotype. Our findings highlight the involvement of CD99 in crucial processes of cancer malignancy, serving as a curtain raiser for this, so far neglected molecule. In addition, a dualistic role for the two CD99 isoforms was shown in agreement with what was observed for other cell adhesion molecules. | D002471 | Cell Transformation, Neoplastic |
| SRC | 17471235 | CD99 isoforms dictate opposite functions in tumour malignancy and metastases by activating or repressing c-Src kinase activity. | CD99 gene encodes two distinct proteins, produced by alternative splicing of CD99 gene transcript. Full-length CD99 isoform (CD99wt) is formed by an extracellular domain, followed by a transmembrane domain and a 36 amino-acid intracytoplasmic domain, which is partially deleted in the truncated, short form (CD99sh). A differential expression of these two CD99 molecules can lead to distinct functional outcomes in lymphocytes. To investigate the functional effects of CD99 molecules on malignancy, forced overexpression of the two CD99 isoforms was induced in osteosarcoma and prostate cancer cells. The two isoforms exhibited opposite functions: the major form dramatically inhibits anchorage-independent growth, anoikis resistance, migration and metastasis, whereas the CD99sh remarkably favours the phenomena. A mechanistic analysis of CD99-transfected osteosarcoma cells points to involvement of c-Src family kinase activity in regulating CD99 functions in malignancy. Ser168 residue of CD99 plays a pivotal role in the reversion of the malignant phenotype. Our findings highlight the involvement of CD99 in crucial processes of cancer malignancy, serving as a curtain raiser for this, so far neglected molecule. In addition, a dualistic role for the two CD99 isoforms was shown in agreement with what was observed for other cell adhesion molecules. | D009362 | Neoplasm Metastasis |
| SRC | 17471235 | CD99 isoforms dictate opposite functions in tumour malignancy and metastases by activating or repressing c-Src kinase activity. | CD99 gene encodes two distinct proteins, produced by alternative splicing of CD99 gene transcript. Full-length CD99 isoform (CD99wt) is formed by an extracellular domain, followed by a transmembrane domain and a 36 amino-acid intracytoplasmic domain, which is partially deleted in the truncated, short form (CD99sh). A differential expression of these two CD99 molecules can lead to distinct functional outcomes in lymphocytes. To investigate the functional effects of CD99 molecules on malignancy, forced overexpression of the two CD99 isoforms was induced in osteosarcoma and prostate cancer cells. The two isoforms exhibited opposite functions: the major form dramatically inhibits anchorage-independent growth, anoikis resistance, migration and metastasis, whereas the CD99sh remarkably favours the phenomena. A mechanistic analysis of CD99-transfected osteosarcoma cells points to involvement of c-Src family kinase activity in regulating CD99 functions in malignancy. Ser168 residue of CD99 plays a pivotal role in the reversion of the malignant phenotype. Our findings highlight the involvement of CD99 in crucial processes of cancer malignancy, serving as a curtain raiser for this, so far neglected molecule. In addition, a dualistic role for the two CD99 isoforms was shown in agreement with what was observed for other cell adhesion molecules. | D009369 | Neoplasms |
| SRC | 17471235 | CD99 isoforms dictate opposite functions in tumour malignancy and metastases by activating or repressing c-Src kinase activity. | CD99 gene encodes two distinct proteins, produced by alternative splicing of CD99 gene transcript. Full-length CD99 isoform (CD99wt) is formed by an extracellular domain, followed by a transmembrane domain and a 36 amino-acid intracytoplasmic domain, which is partially deleted in the truncated, short form (CD99sh). A differential expression of these two CD99 molecules can lead to distinct functional outcomes in lymphocytes. To investigate the functional effects of CD99 molecules on malignancy, forced overexpression of the two CD99 isoforms was induced in osteosarcoma and prostate cancer cells. The two isoforms exhibited opposite functions: the major form dramatically inhibits anchorage-independent growth, anoikis resistance, migration and metastasis, whereas the CD99sh remarkably favours the phenomena. A mechanistic analysis of CD99-transfected osteosarcoma cells points to involvement of c-Src family kinase activity in regulating CD99 functions in malignancy. Ser168 residue of CD99 plays a pivotal role in the reversion of the malignant phenotype. Our findings highlight the involvement of CD99 in crucial processes of cancer malignancy, serving as a curtain raiser for this, so far neglected molecule. In addition, a dualistic role for the two CD99 isoforms was shown in agreement with what was observed for other cell adhesion molecules. | D012516 | Osteosarcoma |
| SRC | 17471235 | CD99 isoforms dictate opposite functions in tumour malignancy and metastases by activating or repressing c-Src kinase activity. | CD99 gene encodes two distinct proteins, produced by alternative splicing of CD99 gene transcript. Full-length CD99 isoform (CD99wt) is formed by an extracellular domain, followed by a transmembrane domain and a 36 amino-acid intracytoplasmic domain, which is partially deleted in the truncated, short form (CD99sh). A differential expression of these two CD99 molecules can lead to distinct functional outcomes in lymphocytes. To investigate the functional effects of CD99 molecules on malignancy, forced overexpression of the two CD99 isoforms was induced in osteosarcoma and prostate cancer cells. The two isoforms exhibited opposite functions: the major form dramatically inhibits anchorage-independent growth, anoikis resistance, migration and metastasis, whereas the CD99sh remarkably favours the phenomena. A mechanistic analysis of CD99-transfected osteosarcoma cells points to involvement of c-Src family kinase activity in regulating CD99 functions in malignancy. Ser168 residue of CD99 plays a pivotal role in the reversion of the malignant phenotype. Our findings highlight the involvement of CD99 in crucial processes of cancer malignancy, serving as a curtain raiser for this, so far neglected molecule. In addition, a dualistic role for the two CD99 isoforms was shown in agreement with what was observed for other cell adhesion molecules. | D011471 | Prostatic Neoplasms |
| SRC | 23949219 | MBNL142 and MBNL143 gene isoforms, overexpressed in DM1-patient muscle, encode for nuclear proteins interacting with Src family kinases. | Myotonic dystrophy type-1 (DM1) is the most prevalent form of muscular dystrophy in adults. This disorder is an RNA-dominant disease, caused by expansion of a CTG repeat in the DMPK gene that leads to a misregulation in the alternative splicing of pre-mRNAs. The longer muscleblind-like-1 (MBNL1) transcripts containing exon 5 and the respective protein isoforms (MBNL142-43) were found to be overexpressed in DM1 muscle and localized exclusively in the nuclei. In vitro assays showed that MBNL142-43 bind the Src-homology 3 domain of Src family kinases (SFKs) via their proline-rich motifs, enhancing the SFK activity. Notably, this association was also confirmed in DM1 muscle and myotubes. The recovery, mediated by an siRNA target to Ex5-MBNL142-43, succeeded in reducing the nuclear localization of both Lyn and MBNL142-43 proteins and in decreasing the level of tyrosine phosphorylated proteins. Our results suggest an additional molecular mechanism in the DM1 pathogenesis, based on an altered phosphotyrosine signalling pathway. | D009223 | Myotonic Dystrophy |
| SRC | 24711643 | Identifying biological pathways that underlie primordial short stature using network analysis. | Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M 'interactome', to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure. | D004392 | Dwarfism |
| SRC | 24711643 | Identifying biological pathways that underlie primordial short stature using network analysis. | Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M 'interactome', to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure. | D006130 | Growth Disorders |
| SRC | 24711643 | Identifying biological pathways that underlie primordial short stature using network analysis. | Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M 'interactome', to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure. | D009123 | Muscle Hypotonia |
Clinically important variants in SRC |
| (ClinVar, 04/20/2024) |
| accession_id | uniprot_id | gene_name | Type | Variant | Clinical_significance |
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