SRC_RAT - PTM Information in dbPTM

Basic Information of Protein

• UniProt ID: SRC_RAT
• UniProt AC: Q9WUD9
• Protein Name: Proto-oncogene tyrosine-protein kinase Src
• Gene Name: Src
• Organism: Rattus norvegicus (Rat).
• Sequence Length: 536
• Subcellular Localization: Cell membrane . Mitochondrion inner membrane . Nucleus . Cytoplasm, cytoskeleton . Cytoplasm, perinuclear region . Localizes to focal adhesion sites following integrin engagement. Localization to focal adhesion sites requires myristoylation and the S
• Protein Description: Non-receptor protein tyrosine kinase which is activated following engagement of many different classes of cellular receptors including immune response receptors, integrins and other adhesion receptors, receptor protein tyrosine kinases, G protein-coupled receptors as well as cytokine receptors. Participates in signaling pathways that control a diverse spectrum of biological activities including gene transcription, immune response, cell adhesion, cell cycle progression, apoptosis, migration, and transformation. Due to functional redundancy between members of the SRC kinase family, identification of the specific role of each SRC kinase is very difficult. SRC appears to be one of the primary kinases activated following engagement of receptors and plays a role in the activation of other protein tyrosine kinase (PTK) families. Receptor clustering or dimerization leads to recruitment of SRC to the receptor complexes where it phosphorylates the tyrosine residues within the receptor cytoplasmic domains. Plays an important role in the regulation of cytoskeletal organization through phosphorylation of specific substrates such as AFAP1. Phosphorylation of AFAP1 allows the SRC SH2 domain to bind AFAP1 and to localize to actin filaments. Cytoskeletal reorganization is also controlled through the phosphorylation of cortactin (CTTN) (Probable). When cells adhere via focal adhesions to the extracellular matrix, signals are transmitted by integrins into the cell resulting in tyrosine phosphorylation of a number of focal adhesion proteins, including PTK2/FAK1 and paxillin (PXN) (By similarity). In addition to phosphorylating focal adhesion proteins, SRC is also active at the sites of cell-cell contact adherens junctions and phosphorylates substrates such as beta-catenin (CTNNB1), delta-catenin (CTNND1), and plakoglobin (JUP). Another type of cell-cell junction, the gap junction, is also a target for SRC, which phosphorylates connexin-43 (GJA1). SRC is implicated in regulation of pre-mRNA-processing and phosphorylates RNA-binding proteins such as KHDRBS1 (Probable). Also plays a role in PDGF-mediated tyrosine phosphorylation of both STAT1 and STAT3, leading to increased DNA binding activity of these transcription factors (By similarity). Involved in the RAS pathway through phosphorylation of RASA1 and RASGRF1. Plays a role in EGF-mediated calcium-activated chloride channel activation (By similarity). Required for epidermal growth factor receptor (EGFR) internalization through phosphorylation of clathrin heavy chain (CLTC and CLTCL1) at 'Tyr-1477'. Involved in beta-arrestin (ARRB1 and ARRB2) desensitization through phosphorylation and activation of GRK2, leading to beta-arrestin phosphorylation and internalization. Has a critical role in the stimulation of the CDK20/MAPK3 mitogen-activated protein kinase cascade by epidermal growth factor (Probable). Might be involved not only in mediating the transduction of mitogenic signals at the level of the plasma membrane but also in controlling progression through the cell cycle via interaction with regulatory proteins in the nucleus. Plays an important role in osteoclastic bone resorption in conjunction with PTK2B/PYK2. Both the formation of a SRC-PTK2B/PYK2 complex and SRC kinase activity are necessary for this function. Recruited to activated integrins by PTK2B/PYK2, thereby phosphorylating CBL, which in turn induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function. Promotes energy production in osteoclasts by activating mitochondrial cytochrome C oxidase (By similarity). Phosphorylates DDR2 on tyrosine residues, thereby promoting its subsequent autophosphorylation. [PubMed: 16186108 Phosphorylates RUNX3 and COX2 on tyrosine residues, TNK2 on 'Tyr-284' and CBL on 'Tyr-738'. Enhances DDX58/RIG-I-elicited antiviral signaling. Phosphorylates PDPK1 at 'Tyr-9', 'Tyr-373' and 'Tyr-376'. Phosphorylates BCAR1 at 'Tyr-226'. Phosphorylates CBLC at multiple tyrosine residues, phosphorylation at 'Tyr-341' activates CBLC E3 activity. Involved in anchorage-independent cell growth (By similarity Required for podosome formation (By similarity]
• Protein Sequence: MGSNKSKPKDASQRRRSLEPAENVHGAGGAFPASQTPSKPASADGHRGPNAAFVPPAAAEPKLFGGFNSSDTVTSPQRAGPLAGGVTTFVALYDYESRTETDLSFKKGERLQIVNNTEGDWWLAHSLSTGQTGYIPSNYVAPSDSIQAEEWYFGKITRRESERLLLNAENPRGTFLVRESETTKGAYCLSVSDFDNAKGLNVKHYKIRKLDSGGFYITSRTQFNSLQQLVAYYSKHADGLCHRLTTVCPTSKPQTQGLAKDAWEIPRESLRLEVKLGQGCFGEVWMGTWNGTTRVAIKTLKPGTMSPEAFLQEAQVMKKLRHEKLVQLYAVVSEEPIYIVTEYMNKGSLLDFLKGETGKYLRLPQLVDMSAQIASGMAYVERMNYVHRDLRAANILVGENLVCKVADFGLARLIEDNEYTARQGAKFPIKWTAPEAALYGRFTIKSDVWSFGILLTELTTKGRVPYPGMVNREVLDQVERGYRMPCPPECPESLHDLMCQCWRKEPEERPTFEYLQAFLEDYFTSTEPQYQPGENL

Overview of Protein Modification Sites with Functional and Structural Information

Experimental Post-Translational Modification Sites

* ASA = Accessible Surface Area

Locations	Modification	Substrate Peptides & Secondary Structure	ASA (%)	Reference
2	Myristoylation	------MGSNKSKPK ------CCCCCCCCC	39.67	-
17	Phosphorylation	DASQRRRSLEPAENV CHHHHHHCCCCCCCC	34.96	23712012
34	Phosphorylation	AGGAFPASQTPSKPA CCCCCCCCCCCCCCC	34.52	28432305
36	Phosphorylation	GAFPASQTPSKPASA CCCCCCCCCCCCCCC	27.34	28432305
38	Phosphorylation	FPASQTPSKPASADG CCCCCCCCCCCCCCC	55.44	28432305
42	Phosphorylation	QTPSKPASADGHRGP CCCCCCCCCCCCCCC	35.11	28432305
69	Phosphorylation	KLFGGFNSSDTVTSP CCCCCCCCCCCCCCC	27.59	28551015
70	Phosphorylation	LFGGFNSSDTVTSPQ CCCCCCCCCCCCCCC	38.10	28551015
72	Phosphorylation	GGFNSSDTVTSPQRA CCCCCCCCCCCCCCC	27.86	27097102
74	Phosphorylation	FNSSDTVTSPQRAGP CCCCCCCCCCCCCCC	36.46	27097102
75	Phosphorylation	NSSDTVTSPQRAGPL CCCCCCCCCCCCCCC	18.07	30411139
93	Phosphorylation	VTTFVALYDYESRTE CEEEEEEEECCCCCC	13.52	22276854
187	Phosphorylation	SETTKGAYCLSVSDF CCCCCCEEEEEHHHC	11.55	-
216	Phosphorylation	KLDSGGFYITSRTQF ECCCCCEEEEEHHHC	13.43	16769082
232	Phosphorylation	SLQQLVAYYSKHADG CHHHHHHHHHHCCCC	10.78	-
252	Ubiquitination	TTVCPTSKPQTQGLA EEECCCCCCCCCCCC	43.56	-
419	Phosphorylation	RLIEDNEYTARQGAK HHHCCCCCCCCCCCC	16.38	11907028
420	Phosphorylation	LIEDNEYTARQGAKF HHCCCCCCCCCCCCC	14.80	27097102
426	Acetylation	YTARQGAKFPIKWTA CCCCCCCCCCCEECC	59.50	-
439	Phosphorylation	TAPEAALYGRFTIKS CCCCHHHHCCEEEEH	11.09	27097102
511	Phosphorylation	KEPEERPTFEYLQAF CCCCCCCHHHHHHHH	35.01	-
522	Phosphorylation	LQAFLEDYFTSTEPQ HHHHHHHHHCCCCCC	10.20	-
525	Phosphorylation	FLEDYFTSTEPQYQP HHHHHHCCCCCCCCC	20.55	22673903
526	Phosphorylation	LEDYFTSTEPQYQPG HHHHHCCCCCCCCCC	31.93	22673903
530	Phosphorylation	FTSTEPQYQPGENL- HCCCCCCCCCCCCC-	23.93	11907028

Upstream regulatory proteins (kinases for phosphorylation sites, E3 ubiquitin ligases of ubiquitination sites, ...)

Modified Location	Modified Residue	Modification	Type of Upstream Proteins	Gene Name of Upstream Proteins	UniProt AC of Upstream Proteins	Sources
75	S	Phosphorylation	Kinase	CDK5	Q03114	Uniprot
419	Y	Phosphorylation	Kinase	PTK2B	P70600	GPS
419	Y	Phosphorylation	Kinase	SRC	P12931	PSP
530	Y	Phosphorylation	Kinase	CSK	P32577	Uniprot
530	Y	Phosphorylation	Kinase	SRC	Q9WUD9	PSP

Functions of PTM Sites

Modified Location	Modified Residue	Modification	Function	Reference
2	G	Myristoylation	Myristoylated at Gly-2, and this is essential for targeting to membranes.	-
75	S	Phosphorylation	CDK5-mediated phosphorylation at Ser-75 targets SRC to ubiquitin-dependent degradation and thus leads to cytoskeletal reorganization.	8849729
75	S	ubiquitylation	CDK5-mediated phosphorylation at Ser-75 targets SRC to ubiquitin-dependent degradation and thus leads to cytoskeletal reorganization.	8849729

Disease-associated PTM Sites based on SAP

* Distance = the distance between SAP position and PTM sites.

Oops, there are no SNP-PTM records of SRC_RAT !!

Protein-Protein Interaction

Interacting Protein	Gene Name	Interaction Type	PPI Reference
PLD2_RAT	Pld2	physical	15705590
AGTRA_RAT	Agtr1a	physical	16151024
SRC_RAT	Src	physical	16511561
CSK_RAT	Csk	physical	16511561
CELF2_RAT	Celf2	physical	17855367
SRC_RAT	Src	physical	17855367

Drug and Disease Associations

• Kegg Drug
• DrugBank
• There are no disease associations of PTM sites.

Related Literatures of Post-Translational Modification

Phosphorylation

"A role for Pyk2 and Src in linking G-protein-coupled receptors withMAP kinase activation.";
Dikic I., Tokiwa G., Lev S., Courtneidge S.A., Schlessinger J.;
Nature 383:547-550(1996).
Cited for: INTERACTION WITH PTK2B/PYK2, ENZYME REGULATION, AND PHOSPHORYLATION ATTYR-419.
PubMed: 8849729