Schematic representation of the role of receptor tyrosine kinases (RTKs) in ureteric bud morphogenesis (UB) and kidney development. Growth factor ligands bind simultaneously with two cognate cell surface RTK molecules and cross-link them into a dimeric complex. This is followed by phosphorylation (P) of critical tyrosine (Y) residues of the intracellular tyrosine kinase domain, recruitment of specific docking proteins, and activation of intracellular signaling cascades. VEGFR2 heterodimerizes with Ret and induces P of Y1062Ret [1]. Angiotensin (Ang) II, acting via the AT1 receptor (AT1R), transactivates EGFR and Y1062Ret and stimulates their downstream signaling via the PI3K/Akt and Erk1/2 pathways to induce UB branching [2, 3]. In context of UB morphogenesis, induction of Ret activity is mediated by Ang II-induced downregulation of Spry1, a physiological inhibitor of RTK signaling [4, 5]. Please see text for details.
