Signaling Coupling Between GPCR and RTK

Kyong-Tai Kim

Department of Life Science, POSTECH, Pohang, 790-784, Korea

e-mail: ktk@postech.ac.kr

Ca²⁺ is a highly versatile intracellular signal that regulates many different cellular processes, and cells have developed mechanisms to have exquisite control over Ca²⁺ signaling. Communication between receptor tyrosine kinase (RTK)- and G protein-coupled receptor (GPCR)-mediated Ca²⁺ signaling systems has received increasing attention. Epidermal growth factor (EGF), which fails to mobilize intracellular Ca²⁺ when administrated alone, becomes capable of evoking [Ca²⁺]_i increase and exocytosis after bradykinin (BK) stimulation in chromaffin cells. Here, we provide evidence that this sensitization process is coordinated by a macromolecular signaling complex comprised of inositol 1,4,5-trisphosphate receptor type I (IP₃R1), cAMP-dependent protein kinase (PKA), EGF receptor (EGFR), and an A-kinase anchoring protein (AKAP), yotiao. BK caused activation of non-receptor tyrosine kinase p60^Src and Src-dependent phosphorylation of the EGFR on Tyr-845, as well as recruitment of phospholipase Cγ1 which produces IP₃. In addition, the IP₃R complex functions as a focal point to promote Ca²⁺ release in two ways: (i) it facilitates PKA-dependent phosphorylation of IP₃R1 in response to BK-induced elevation of cAMP and (ii) it couples the plasmalemmal EGFR with IP₃R1 at the Ca²⁺ store located juxtaposed to the plasma membrane. Our study illustrates the cross-talk of receptor-mediated signal transduction pathways via signaling complexes in membrane microdomain and how the junctional membrane IP₃R complex connects different signaling pathways to define the fidelity and specificity of Ca²⁺ signaling.