Src family kinase

Src kinase family is a family of non-receptor tyrosine kinases that includes nine members: Src, Yes, Fyn, and Fgr, forming the SrcA subfamily, Lck, Hck, Blk, and Lyn in the SrcB subfamily, and Frk in its own subfamily. Frk has homologs in invertebrates such as flies and worms, and Src homologs exist in organisms as diverse as unicellular choanoflagellates, but the SrcA and SrcB subfamilies are specific to vertebrates. Src family kinases contain six conserved domains: a N-terminal myristoylated segment, a SH2 domain, a SH3 domain, a linker region, a tyrosine kinase domain, and C-terminal tail.^[1]

Src kinase
Identifiers
Symbol	Src
CDD	cd05071
UniProt family PTHR24418:SF53 Example member: P12931

Src family kinases interact with many cellular cytosolic, nuclear and membrane proteins, modifying these proteins by phosphorylation of tyrosine residues. A number of substrates have been discovered for these enzymes.^[2][3][4] Deregulation, including constitutive activation or over expression, may contribute to the progression of cellular transformation and oncogenic activity.^[5]

Structure

Src family kinases contain six distinct domains including a myristoylated N-terminal segment, an SH2 domain, an SH3 domain, a linker region, a tyrosine kinase domain, and a C-terminal tail. Src kinases are known for having a characteristically short C-terminal tail that contains an autoinhibitory phosphorylation site. The SH2 and SH3 domains exist in a conformation that locks the catalytic domain into an inactive state.

Myristoylated N-terminus

Myristoylation is a post-translational modification marked by the covalent attachment of a myristoyl group to an N-terminal glycine residue. It allows for weak protein-protein and protein-lipid interactions. Myristoylation aids in the membrane association of Src kinases.

SH2 and SH3 domains

The SH2 domain of Src family kinases consist of approximately 100 amino acids. This domain acts by binding to phosphorylated tyrosine residues. The strength of binding is dependent on the amino acids surrounding the phosphorylated tyrosine. The Src kinases Fyn, Src, and Yes all bind via their SH2 domains. SH2 domains of Src family kinases play an important role in binding to growth factor receptors as well as regulating the activity of Src kinases.^[6]

Linker region

The linker region of Src kinase consists of a SH2-kinase linker which intercalates between the SH3 domain and the N-terminal domain lobe. When comparing the linker regions of various members of the Src family, they were found to have little sequence similarity ^[7]

Tyrosine kinase domain

Tyrosine kinase domains selectively phosphorylate tyrosine residues. The tyrosine kinase domain of Src contains around 300 amino acid residues and consists of an N-terminal lobe with β-sheets and α-helices, and a C-terminal lobe that is composed primarily of α-helices.^[8]

C-terminal tail

The C-terminal tail is a location of phosphorylation and dephosphorylation in Src family kinases. In c-Src, this occurs at the tyrosine residue 527. When looking at other Src molecules, most are phosphorylated at this tyrosine residue by action of the Csk family protein kinases.  

Mechanism

Activation

Src kinases are activated through a variety of ligands binding to the SH2 and SH3 domains. They can also be activated through the SH3 domain being displaced while SH2 remains engaged with the C-terminal tail. Src can be activated by receptor tyrosine kinases such as EGFR and HGF receptors. Src kinases are recruited to and activated by these receptors through the interaction of its SH2 domain with the phosphorylated tyrosine receptor. Src kinases can also be activated through displacement of their SH3 domain. When this occurs, the SH2 domains stay in contact with the C-terminal tail. An absence of regulatory proteins will also affect Src's ability to be activated properly.

Localization

Subcellular localization of Src kinases indicate their function. Src is known to associate with cell membranes, specifically the plasma membrane, the perinuclear membrane, and endosomal membranes.^[9] Membrane association is partly due to the myristoyl group at the N-terminus being able to covalently attach to the membranes. Other amino acid residues at the N-terminus are important for membrane association as well because they allow Src to associate with fusion protein constructs. Myristoylation and fusion proteins work together to localize Src to cellular membranes.

Function

Src kinases transduce signals related to cellular processes such as proliferation, differentiation, motility, and adhesion. Src kinase activation leads to an increase in these processes, so Src's functionality is linked to human cancer development.^[10] Inhibiting Src kinases is often a target or goal of anti-cancer drugs.

STATs and Src family kinase

Signal transducers and activators of transcription (STATs) are activated by Src family kinases in addition to growth factor receptors. STAT activation by Src family kinases often occurs downstream of growth factor receptor kinases. It has been shown that Src kinase activity is oftentimes for EGF signaling. The activation of STAT is a known requirement for tumor proliferation.

Breast cancer model

70% of breast cancer cells overexpress tyrosine kinases (specifically c-Src). A combination of c-Src and EGFR are often co-expressed in later stage tumors. This co-expression leads to a synergistic increase in mitogenesis, transformation, and tumorigenesis. Specifically, it has been found that Tyr845 in the catalytic domain of EGFR is not auto-phosphorylated. Later, it requires an association of c-Src with EGFR as well as the kinase activity of c-Src.

See also

• Proto-oncogene tyrosine-protein kinase Src
• Myristoylation
• SH2 domain
• SH3 domain

References

1. Parsons SJ, Parsons JT (October 2004). "Src family kinases, key regulators of signal transduction". Oncogene. 23 (48): 7906–9. doi:10.1038/sj.onc.1208160. PMID 15489908.
2. Amanchy R, Zhong J, Hong R, Kim JH, Gucek M, Cole RN, et al. (December 2009). "Identification of c-Src tyrosine kinase substrates in platelet-derived growth factor receptor signaling". Molecular Oncology. 3 (5–6): 439–50. doi:10.1016/j.molonc.2009.07.001. PMC 2783305. PMID 19632164.
3. Amanchy R, Zhong J, Molina H, Chaerkady R, Iwahori A, Kalume DE, et al. (September 2008). "Identification of c-Src tyrosine kinase substrates using mass spectrometry and peptide microarrays". Journal of Proteome Research. 7 (9): 3900–10. doi:10.1021/pr800198w. PMC 2646669. PMID 18698806.
4. Luo W, Slebos RJ, Hill S, Li M, Brábek J, Amanchy R, et al. (August 2008). "Global impact of oncogenic Src on a phosphotyrosine proteome". Journal of Proteome Research. 7 (8): 3447–60. doi:10.1021/pr800187n. PMC 2579752. PMID 18563927.
5. Zhang S, Yu D (March 2012). "Targeting Src family kinases in anti-cancer therapies: turning promise into triumph". Trends in Pharmacological Sciences. 33 (3): 122–8. doi:10.1016/j.tips.2011.11.002. PMC 3675659. PMID 22153719.
6. Alonso G, Koegl M, Mazurenko N, Courtneidge SA (April 1995). "Sequence requirements for binding of Src family tyrosine kinases to activated growth factor receptors". The Journal of Biological Chemistry. 270 (17): 9840–8. doi:10.1074/jbc.270.17.9840. PMID 7730365.
7. Williams JC, Wierenga RK, Saraste M (May 1998). "Insights into Src kinase functions: structural comparisons". Trends in Biochemical Sciences. 23 (5): 179–84. doi:10.1016/S0968-0004(98)01202-X. PMID 9612082.
8. Paul MK, Mukhopadhyay AK (2004). "Tyrosine kinase - Role and significance in Cancer". International Journal of Medical Sciences. 1 (2): 101–115. doi:10.7150/ijms.1.101. PMC 1074718. PMID 15912202.
9. Bjorge JD, Jakymiw A, Fujita DJ (November 2000). "Selected glimpses into the activation and function of Src kinase". Oncogene. 19 (49): 5620–35. doi:10.1038/sj.onc.1203923. PMID 11114743.
10. Irby RB, Yeatman TJ (November 2000). "Role of Src expression and activation in human cancer". Oncogene. 19 (49): 5636–42. doi:10.1038/sj.onc.1203912. PMID 11114744.