Src

**Discovery/History:** Rous sarcoma virus (Peyton Rous, 1911; Nobel 1966). v-src was the first viral oncogene identified; Bishop and Varmus (Nobel 1989) showed the cellular homolog c-src is a normal host gene (proto-oncogene), establishing that retroviral oncogenes are captured/mutated host genes.

**Structure and regulation:** Src family kinases (SFKs: Src, Fyn, Yes, Lck, Lyn, Hck, Fgr, Blk) share SH3, SH2, and SH1 (catalytic kinase) domains and an N-terminal myristoylation site for membrane anchoring. - Inactive state: Csk (C-terminal Src kinase) phosphorylates Tyr527 (chicken numbering; Tyr530 in human), which binds the Src's own SH2 domain and keeps it in a closed, inactive conformation. - Activation: dephosphorylation of Tyr527 (by phosphatases such as CD45 or PTP) plus autophosphorylation of Tyr416 (activation loop; Tyr419 in human) opens the conformation and activates the kinase. - v-Src lacks the C-terminal regulatory tyrosine, so it is constitutively active.

**Function:** Downstream of receptor tyrosine kinases (EGFR, PDGFR), integrins/focal adhesion kinase (FAK), and GPCRs. Signals through Ras/MAPK, PI3K/Akt, and STAT3 to promote proliferation, survival, angiogenesis (VEGF), cell motility, and invasion/metastasis. Also essential for osteoclast function (Src-/- mice develop osteopetrosis).

**Clinical significance:** - Oncogene class: non-receptor tyrosine kinase (other examples: Abl, Janus kinase/JAK, BTK). Overexpression or activation is seen in colon, breast, pancreatic, and prostate cancers. - Abl/Bcr-Abl (CML, Philadelphia chromosome t(9;22)) is also a non-receptor tyrosine kinase and is related to Src family signaling. Dasatinib inhibits both Bcr-Abl and Src family kinases and is used in imatinib-resistant CML and Ph+ ALL. Bosutinib is also a dual Src/Abl inhibitor. - Lck (SFK) is critical for T-cell receptor signaling (phosphorylates ITAMs, activates ZAP-70). Lyn and Fyn contribute to B-cell and mast cell signaling. - Src is not the same as Sarcoma (Rous sarcoma virus); don't confuse with "SRC" (steroid receptor coactivator) in other contexts.

**High-yield board points:** 1. Src = first proto-oncogene discovered; non-receptor tyrosine kinase. 2. Proto-oncogene → oncogene via gain-of-function (mutation, amplification, translocation, viral capture). 3. Oncogene categories: growth factors (sis), receptor TKs (erbB1/EGFR, HER2/neu, RET, KIT), non-receptor TKs (abl, src), GTPases (ras), transcription factors (myc, fos, jun), cell cycle regulators (cyclins, CDKs), anti-apoptotic (bcl-2). 4. Dasatinib targets Src and Bcr-Abl. 5. Mechanism of viral oncogenesis: v-src is a retroviral transforming gene that lacks the negative regulatory domain.