Intersecting pathways in cell biology

Abstract

The endocytic pathway is involved in activation and inhibition of cellular signaling. Thus, defining the regulatory mechanisms that link endocytosis and cellular signaling is of interest. An emerging link between these processes is a family of proteins called intersectins (ITSNs). These multidomain proteins serve as scaffolds in the assembly of endocytic vesicles and also regulate components of various signaling pathways, including kinases, guanosine triphosphatases, and ubiquitin ligases. This review summarizes research on the role of ITSNs in regulating both endocytic and signal transduction pathways, discusses the link between ITSNs and human disease, and highlights future directions in the study of ITSNs.

Fig. 1

Schematic of ITSN orthologs. Shown are representative members of ITSN proteins from various species. Some ITSN genes encode only a short isoform as indicated by the absence of the DH-PH-C2 modules. The number of ITSN genes in the species is indicated to the right.

Fig. 2

ITSN regulates multiple members of the Ras superfamily of GTPases. The DH-PH domains of ITSN-L directly activates Cdc42. Both isoforms of ITSN interact with Sos, thereby regulating activation of Ras. Sos is also a Rac GEF, and by extension, ITSN might stimulate activation of Rac. ITSN might also indirectly activate Rac and Cdc42 by interacting with and inhibiting CdGAP, a GAP for Rac and Cdc42. ITSN might inhibit additional Cdc42 GAPs through epsins, although the epsin-Cdc42 pathway has not been demonstrated in mammalian cells. Thus, ITSN might serve as a nexus for the regulation of multiple Ras-like GTPase. Solid arrows, link is supported by experimental data; dashed arrows, speculative links.

Fig. 3

Regulation of the polarity complex by ITSN. The ITSN-S and ITSN-L isoforms have been implicated in the regulation of the PAR6-PAR3-aPKC polarity complex.