Calmodulin (CaM) is a calcium sensor protein that directly interacts with the 
dual-specificity (lipid and protein) kinase PI3Kα through the SH2 domains of the 
p85 regulatory subunit. In adenocarcinomas, the CaM interaction removes the 
autoinhibition of the p110 catalytic subunit of PI3Kα, leading to activation of 
PI3Kα and promoting cell proliferation, survival, and migration. Here we 
demonstrate that the cSH2 domain of p85α engages its two CaM-binding motifs in 
the interaction with the N- and C-lobes of CaM as well as the flexible central 
linker, and our nuclear magnetic resonance experiments provide structural 
details. We show that in response to binding CaM, cSH2 exposes its tryptophan 
residue at the N-terminal region to the solvent. Because of the flexible nature 
of both CaM and cSH2, multiple binding modes of the interactions are possible. 
Binding of CaM to the cSH2 domain can help release the inhibition imposed on the 
p110 subunit, similar to the binding of the phosphorylated motif of RTK, or 
phosphorylated CaM (pCaM), to the SH2 domains. Amino acid sequence analysis 
shows that CaM-binding motifs are common in SH2 domains of non-RTKs. We 
speculate that CaM can also activate these kinases through similar mechanisms.