This interaction is enhanced by either BMP2 stimu lation or the Cabozantinib cancer presence of BMPRI whereas the kinase activ ity of BMPRII seems dispensable. This observation may reflect the same mechanism by which BMPRII is incorpo rated into BISCs upon stimulation with BMP2, where the high affinity receptor for BMP2 recruits BMPRII into the complex upon BMP2 binding. More over, we showed previously that BISC mediated sig nalling and BMPRII recruitment towards BMPRI is required for non Smad signalling. We therefore speculate that the BMPRI kinase is required for PI3K acti vation whereas BMPRII acts as a scaffolding hub to pro vide PI3K for BMPRI dependent activation mechanisms that have not yet been defined. This hypothesis is under lined by our previous findings of reduced BMP2 induced Akt phosphorylation upon pharmacological inhibition of BMPRI kinase activity.

BMPRI activity seems crucial in mediating the association of p55�� with BMPRII and, thus, PI3K activity. Research on the related TGF B pathway identified that the high affinity TGF B receptor type II associated constitutively with Inhibitors,Modulators,Libraries p85, whereas the low affinity TGF B type I receptor only associated with p85 in a ligand dependent manner. However, it should be considered that BMPRI is the high affinity and BMPRII the low affin ity receptor for BMP2. This would therefore represent Inhibitors,Modulators,Libraries a mirror image scenario of PI3K regulatory subunit inter action in BMP versus TGF B receptors. Tyrosine phos phorylation of BMPRII is essential for an association with class Inhibitors,Modulators,Libraries Ia PI3K p55��.

Despite its classification as a tyrosine like kinase, a BMPRII dual kinase Inhibitors,Modulators,Libraries activity in vivo is still speculative and needs to be proven. Our exper iments have shown that BMP2 stimulation rapidly induces BMPRII tyrosine phosphorylation in vitro, comparable to the kinetics of Smad158 phosphorylation via a yet unknown mechanism. Moreover, we identified BMPRII tyrosine residues that could act as direct putative SH2 do main docking sites. Since the interaction site for p55�� could be mapped to the BMPRII kinase, we speculate that pTyr motifs in the BMPRII kinase domain are required for its interaction. However, with the techniques applied here, we cannot comment on potential intermediate adaptor proteins or additional tyrosine kinases facilitating p55�� interaction Inhibitors,Modulators,Libraries and BMP2 dependent BMPRII tyrosine phosphorylation respectively. Along the same line, studies on the related activin pathway have already suggested the involvement of additional adaptor proteins that facilitate the interaction of PI3K regulatory subunits to the activin receptor ActRII. The tyrosine kinases TrkC and Src also interact with BMPRII and could thus facili tate or mediate Volasertib cancer its tyrosine phosphorylation at sites re quired for the interaction to p55��.