FunctionPromotes the exchange of GDP by GTP. Activates specific Rho GTPase family members, thereby inducing various signaling mechanisms that regulate neuronal shape, growth, and plasticity, through their effects on the actin cytoskeleton. Induces lamellipodia independent of its GEF activity.
Tissue specificityIsoform 2 is brain specific. Highly expressed in cerebral cortex, putamen, amygdala, hippocampus and caudate nucleus. Weakly expressed in brain stem and cerebellum. Isoform 4 is expressed in skeletal muscle.
Involvement in diseaseGenetic variation in KALRN is associated with susceptibility to coronary heart disease type 5 (CHDS5) [MIM:608901]. CHD is the leading cause of death and disability worldwide. CHD is multifactorial disease with a strong genetic component. Classic epidemiologic studies have revealed many risk factors for CHD, including age, sex, hypertension, dyslipidemia, diabetes mellitus, smoking, and physical inactivity.
Sequence similaritiesBelongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. Contains 1 CRAL-TRIO domain. Contains 2 DH (DBL-homology) domains. Contains 1 fibronectin type-III domain. Contains 1 Ig-like C2-type (immunoglobulin-like) domain. Contains 2 PH domains. Contains 1 protein kinase domain. Contains 2 SH3 domains. Contains 5 spectrin repeats.
DomainThe two GEF domains catalyze nucleotide exchange for RAC1 and RhoA which are bound by DH1 and DH2 respectively. The two GEF domains appear to play differing roles in neuronal development and axonal outgrowth. SH3 1 binds to the first GEF domain inhibiting GEF activity only when in the presence of a PXXP peptide, suggesting that the SH3 domain/peptide interaction mediates binding to GEF1. CRK1 SH3 domain binds to and inhibits GEF1 activity.