A dynamic interaction between GTPases ras and rap determines signaling in beta-cells

Abstract

Glucose and the incretin hormone glucagon-like peptide-1 (GLP-1) act synergistically as growth factors for insulin-producing b-cells by unknown mechanisms. We examined the involvement of small GTPases ras and rap1 to mitogenic signaling in the b-cell line INS-1E and primary human b-cell preparations. Here, we show that at unfavourable conditions for b-cell growth such as low glucose concentration (2.5 mM), ras is the major activator of MAPK and CREB signaling whereas contribution of rap to MAPK and CREB is minor or even inhibitory to signaling by ras. In contrast, when b-cells are cultivated at favourable growth conditions such as 15 mM glucose or by co-stimulation with GLP-1, the function of rap1 switches from an inhibitor to an activator of CREB and MAPK signaling in concert with ras. These synergistic effects of ras and rap are mediated by differential pleiotropic activation of raf-1, B-raf, PKA and PI3K by both GTPases with a prominent role for rap as a highly regulated central effector of PKA and PI3K. Thus, rap may either act as an inhibitor or an co-activator of ras in a single cell type. Differential downstream signaling by ras and rap1 serves as a balance to mediate synergism of mitogenic signaling between glucose and incretin hormones in pancreatic b-cells providing a therapeutic target for b-cell growth in diabetes mellitus.