Fig. 8.
IQGAP1 regulates cell homeostasis through mTORC1. A model depicting the action of IQGAP1 in coupling cell growth and division through a previously unidentifed CDC42-mTORC1–S6K1–Akt1 pathway in response to nutrient or mitogenic signal. Black arrows and lines denote previously identified regulation of cell size by IQGAP1 and a known mTORC1–S6K1 negative feedback loop (NFL), and red arrows and lines denote new finings in this study. In closed conformation, IQGAP1 enhances insulin secretion, protein synthesis and cell growth (Rittmeyer et al., 2008; Wang et al., 2009) through mTORC1–S6K1. In open conformation IQGAP1-P promotes cell division and proliferation (Wang et al., 2009) through IQGAP1 S1443-P↑, mTORC1 and S6K1↓, and Akt1 S473-P↑ and suppresses differentiation and/or apoptosis by attenuating ERK1/2 and GSK3α/β. IQGAP1 attenuates S6K1 T389-P activity to enhance Akt1 S473-P activity, which in turn activates mitosis where IQGAP1 has a role in cell abscission. Thus IQGAP1 may act like a rheostat to modulate the NFL of S6K1 T389-P→Akt1 S473-P and maintain cell homeostasis, dysregulation of which could underlie tumorigenesis and/or aberrant insulin signaling in diabetes.