How does SHIP1/2 balance PtdIns(3,4)P₂ and does it signal independently of its phosphatase activity?

Abstract

The number of cellular events identified as being directly or indirectly modulated by phosphoinositides dramatically increased in the recent years. Part of the complexity results from the fact that the seven phosphoinositides play second messenger functions in many different areas of growth factors and insulin signaling, cytoskeletal organization, membrane dynamics, trafficking, or nuclear signaling. PtdIns(3,4)P2 is commonly reported as a product of the SH2 domain-containing inositol 5-phosphatases 1/2 (SHIP1 and SHIP2) that dephosphorylate PtdIns(3,4,5)P3 at the 5-position. Here we discuss recent interest in PtdIns(3,4)P2 signaling highlighting its involvement in key cellular mechanisms such as cell adhesion, migration, and cytoskeletal regulation. We question and discuss the involvement of SHIP2 either as a PI 5-phosphatase or as a scaffold protein in insulin signaling, cytoskeletal dynamics, and endocytosis of growth factor receptors.

Phosphatidylinositol (3,4) bisphosphate-specific phosphatases and effector proteins: A distinct branch of PI3K signaling

“…selectively hydrolyzed cellular PI(3,4)P2 but not other phosphoinositides including PI(3)P, PI(4,5)P2 and PI (3,4,5)P3, confirming that PI (3,4)P2 is the preferred substrate of INPP4 in vivo [5,[22][23][24][25].…”

“…INPP4A was proposed to contain two C2 domains in tandem, which bind PI (3,4)P2 and to a lesser extent PI(4)P and phosphatidylserine (PS) and are required for PI(3,4)P2 4-phosphatase activity [24]. The INPP4B C2 domain binds phosphatidic acid and PIP3 [26].…”

“…More recent work determined the in vivo substrate specificity of INPP4 and performed detailed characterization of INPP4 overexpression intended as a genetic tool to specifically turn off PI (3,4)P2 signaling. Consistent with previous in vitro data, INPP4…”

“…A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 5 that selectively remove the phosphate group at position 4 of the inositol ring from PI (3,4)P2 in vitro [18][19][20][21][22]. More recent work determined the in vivo substrate specificity of INPP4 and performed detailed characterization of INPP4 overexpression intended as a genetic tool to specifically turn off PI (3,4)P2 signaling.…”

Les phosphoinositides

“…Actuellement, le PtdIns5P, par ses capacités à coordonner plusieurs mécanismes cellulaires, suscite beaucoup d'intérêt. [18]. Une autre voie de biosynthèse pourrait impliquer les PI3K de classe II et leur substrat, le PtdIns4P, pour contrôler l'endocytose dépendant de la clathrine [19].…”