Intersectin-1s deficiency in pulmonary pathogenesis

Abstract

Intersectin-1s (ITSN-1s), a multidomain adaptor protein, plays a vital role in endocytosis, cytoskeleton rearrangement and cell signaling. Recent studies have demonstrated that deficiency of ITSN-1s is a crucial early event in pulmonary pathogenesis. In lung cancer, ITSN-1s deficiency impairs Eps8 ubiquitination and favors Eps8-mSos1 interaction which activates Rac1 leading to enhanced lung cancer cell proliferation, migration and metastasis. Restoring ITSN-1s deficiency in lung cancer cells facilitates cytoskeleton changes favoring mesenchymal to epithelial transformation and impairs lung cancer progression. ITSN-1s deficiency in acute lung injury leads to impaired endocytosis which leads to ubiquitination and degradation of growth factor receptors such as Alk5. This deficiency is counterbalanced by microparticles which, via paracrine effects, transfer Alk5/TGFβRII complex to non-apoptotic cells. In the presence of ITSN-1s deficiency, Alk5-restored cells signal via Erk1/2 MAPK pathway leading to restoration and repair of lung architecture. In inflammatory conditions such as pulmonary artery hypertension, ITSN-1s full length protein is cleaved by granzyme B into EH_ITSN and SH3A-E_ITSN fragments. The EH_ITSN fragment leads to pulmonary cell proliferation via activation of p38 MAPK and Elk-1/c-Fos signaling. In vivo, ITSN-1s deficient mice transduced with EH_ITSN plasmid develop pulmonary vascular obliteration and plexiform lesions consistent with pathological findings seen in severe pulmonary arterial hypertension. These novel findings have significantly contributed to understanding the mechanisms and pathogenesis involved in pulmonary pathology. As demonstrated in these studies, genetically modified ITSN-1s expression mouse models will be a valuable tool to further advance our understanding of pulmonary pathology and lead to novel targets for treating these conditions.

Keywords: Acute lung injury; Eps8; Intersectin-1s; Lung cancer; MAPK; Pulmonary arterial hypertension; Rac1; mSos1.

Fig. 1

The domain structure intersectin-1 (ITSN-1) proteins. ITSN-1 proteins are comprised of Eps15 homology (EH) domains, a coiled-coil (CC) region, and 5 consecutive Src homology 3 (SH3) domains (SH3A, SH3B, SH3C, SH3D, SH3E), each with distinct ligands. A longer splice variant, termed ITSN-1 l, shares all the domains with the shorter spliced isoform, referred to as ITSN-1s, but in addition possesses a C-terminal extension encoding a Dbl-homology domain (DH), a pleckstrin homology (PH) domain and a C2 domain

Fig. 2

Schematic representation of molecular mechanisms involved in intersectin-1s (ITSN-1s) deficiency mediated pulmonary pathogenesis. The domain structure of full-length ITSN-1s is shown; EGFR, epithelial growth factor receptor; GrB, granzyme B; EC, endothelial cell; PAH, pulmonary artery hypertension; Ub, ubiquitin