Specific tyrosine phosphorylations mediate signal-dependent stimulation of SHIP2 inositol phosphatase activity, while the SH2 domain confers an inhibitory effect to maintain the basal activity.
SH2 domain-containing 5-inositol phosphatase (SHIP2) is implicated in the development of type 2 diabetes and cancer. Tyrosine phosphorylation of SHIP2 is shown to enhance its phosphatase activity. Using IP4 as a substrate, we show here that tyrosines 986, 987, and 1135 are critical for EGF-induced stimulation of SHIP2 activity. SHIP2 with a disrupted SH2 domain (R47G mutation) displays higher constitutive activity than wild-type SHIP2. Deletion of the C-terminus region similarly activates SHIP2. Thus, the SH2 domain of SHIP2, in conjunction with the C-terminus, confers an inhibitory effect to maintain a low basal activity, and signal-induced tyrosine phosphorylations overcome this effect to activate SHIP2.
Prasad
Nagendra K
NK
Purdue Cancer Center and Department of Basic Medical Sciences, Purdue University, West Lafayette, Indiana 47907, USA. nprasad@purdue.edu
Werner
Michael E
ME
Decker
Stuart J
SJ
D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D014443:Tyrosine / Q000378:metabolism*; D018909:src Homology Domains
D014443:Tyrosine; D010744:Phosphoric Monoester Hydrolases; C098706:INPPL1 protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases