Exclusive role for p55�� in BMP2 induced PI3K signalling To date, data regarding unique functions of p55�� are poor, mainly because it is speculated that the five differ selleck EPZ-5676 ent PI3K regulatory subunits have redundant functions Inhibitors,Modulators,Libraries and may compensate for each other. The data presented here show that p55�� provides specific functions during BMP2 Inhibitors,Modulators,Libraries induced PI3K signalling. This is underlined by its exclusive association with BMPRII, its BMP2 dependent phosphorylation in the iSH2 domain, and the effects on Akt phosphorylation and cell migration when knock down of p55�� was performed. We have confirmed that, besides p55��, all other class Ia regulatory subunits, namely p85 and p85B, are detectable at the mRNA level in undifferen tiated multipotent C2C12 cells.

A prom inent role for PI3K regulatory subunits during cytoskeletal rearrangements has already been described, especially in the context of actin reorganisation. Interestingly, some studies have proposed that PI3K regulatory subunits provide non redundant signalling functions dependent on their sub cellular localisation within a cell. This is in line with our data, showing Inhibitors,Modulators,Libraries that p55��, but not p85, in teracts and co localises with BMPRII, predominantly at the cell periphery. It still remains unclear how BMPRII se lectivity for p55�� over p85 is achieved. The p55�� high resolution crystal structure has not been determined and the SH2 and iSH2 domains of human p85 and p55�� share about 81. 1% sequence identity. Based on the data presented here, we now propose two possible mechanisms by which BMPRII selectivity for p55�� could occur.

First, our research revealed BMP2 dependent phosphorylation of the conserved Tyr199 within iSH2 of p55��, but not p85. Phosphorylation of p55�� iSH2 could induce struc tural changes, favouring an association of p55�� with BMPRII over that of the p85 SH2 domain. Inhibitors,Modulators,Libraries Second, the N terminal 34 residues of p55�� bind to tubulin. Be cause the p55�� N terminal sequence is unique and not present in p85, it was proposed that this interaction spe cifically recruits p55�� to the cell periphery. During onset of cortical actin rearrangements, microtubule plus ends penetrate the leading edge cytocortex together with actin nucleating factors. The binding of p55�� to mi crotubules, especially at the very tip, could thus provide a sub cellular pool of p55�� for signalling involved Inhibitors,Modulators,Libraries in cortical actin driven lamellipodia http://www.selleckchem.com/products/mek162.html formation. Besides specific functions of the class Ia PI3K regula tory subunits, class I catalytic subunits also attract in creasing attention to provide non redundant signalling functions. The catalytic subunit p110 has been im plicated in BMP2 induced PI3K signalling and cell mi gration by others using a pharmacological targeting approach.