The GIT family of ADP-ribosylation factor GTPase-activating proteins - Functional diversity of GIT2 through alternative splicing

We recently characterized a novel protein, GIT1, that interacts with G prot ein-coupled receptor kinases and possesses ADP-ribosylation factor (ARF) GT Pase-activating protein activity. A second ubiquitously expressed member of the GIT protein family, GIT2, has been identified in data base searches. G IT2 undergoes extensive alternative splicing and exists in at least 10 and potentially as many as 33 distinct forms. The longest form of GIT2 is colin ear with GIT1 and shares the same domain structure, whereas one major splic e variant prominent in immune tissues completely lacks the carboxyl-termina l domain. The other 32 potential variants arise from the independent altern ative splicing of five internal regions in the center of the molecule but s hare both the amino-terminal ARF GTPase-activating protein domain and carbo xyl-terminal domain. Both the long and short carboxyl-terminal variants of GIT2 are active as GTPase-activating proteins for ARF1, and both also inter act with G: protein-coupled receptor kinase 2 and with pal-activated kinase -interacting exchange factors complexed with pal-activated kinase but not w ith paxillin. Cellular overexpression of the longest variant of GIT2 leads to inhibition of beta(2)-adrenergic receptor sequestration, whereas the sho rtest splice variant appears inactive. Although GIT2 shares many properties with GIT1, it also exhibits both structural and functional diversity due t o tissue-specific alternative splicing.