Src Knockout mouse models

Prototype of the SRC family, Src is the mouse ortholog of human SRC and encodes a myristoylated non-receptor tyrosine kinase organized as SH3, SH2 and kinase domains with a carboxy-terminal regulatory tail whose Tyr527 is phosphorylated by CSK to lock an autoinhibited conformation; displacement of that intramolecular clamp by phosphotyrosine ligands or by PTP1B dephosphorylation permits Tyr416 autophosphorylation and full activity downstream of integrins, FAK, EGFR and other receptors. Null mice are viable but osteopetrotic from defective osteoclast ruffled border formation, a phenotype rescued by kinase-dead SRC, which established that scaffolding is separable from catalysis and makes kinase-dead knockins uniquely informative here. Fyn and Yes occupy overlapping substrate space and compensate substantially, with triple deletion perinatally lethal, so compound conditional genetics is essential for signaling endpoints. Reserve conditional nulls for tissue-autonomous adhesion and metastasis questions and use analog-sensitive gatekeeper knockins for chemical genetic specificity.

Src null animals are straightforward to genotype and phenotype when survival is acceptable. They remain a standard background for pharmacology, biomarker, and rescue studies.