New insights into the functions of intersectin-1s

Abstract

Intersectin-1s (ITSN) is a ubiquitously expressed multifunctional protein known as a scaffold and regulator of the general endocytic machinery as well as a critical integrator of cellular signaling pathways. We showed recently that ITSN deficiency triggers a transforming growth factor β (TGFβ)/Alk5 signaling switch, from the canonical Smad 2/3 to the Erk1/2 MAPK pathway; moreover, endocytic impairment induced by ITSN deficiency enhances Alk5 ubiquitination and degradation and elicits TGFβ-paracrine effects mediated by circulating microparticles, leading to endothelial cell survival and increased proliferation. The studies expand our understanding of how ITSN facilitates cross-regulation of signaling pathways and provide insights into the involvement of ITSN deficiency in human disease.

Intersectin scaffold proteins and their role in cell signaling and endocytosis

“…This pathway begins with the capture of TGFβ by TGFβ receptor II dimers, which immediately recruit and catalyze the phosphorylation of a type I receptor (Alk5) dimer. Both dimers form a heterotetrameric complex that can activate either the Smad2/3 proteins or Smad-independent pathways [57] (Figure 4). The canonical TGFβ signaling pathway includes the recruitment of R-Smad by the Smad anchor for receptor activation (SARA), followed by R-Smad dissociation and subsequent activation of Smad2/3.…”

Intersectin-1s deficiency in pulmonary pathogenesis

“…TGFβ is a ubiquitous and multifunctional cytokine which in the setting of lung injury expresses anti-inflammatory properties confined to the extent of septal injury and facilitates recovery [ 71 ]. Alk5 is a widely expressed transforming growth factor β receptor I (TGFβRI) which complexes with TGFβRII when activated by growth factor TGFβ, and activates Smad2 and Smad3 proteins via the canonical TGFβ signaling pathway [ 72 , 73 ]. In normal EC, internalization of Alk5 via clathrin-coated vesicles leads to TGFβ-induced activation of Smad2/3 pathway which is then recycled to the plasma membrane.…”

“…In normal EC, internalization of Alk5 via clathrin-coated vesicles leads to TGFβ-induced activation of Smad2/3 pathway which is then recycled to the plasma membrane. In contrast internalization of Alk5 by caveolae is directed to ubiquitin proteasome pathway [ 73 , 74 ]. The alternative pathways upregulated by ITSN-1s deficiency express predominantly caveolin-1 and therefore alters the endocytic trafficking of Alk5 in favor of enhanced degradation [ 12 ].…”