New insights into the functions of intersectin-1s

Predescu, Sanda; Bardita, Cristina; Predescu, Dan

doi:10.1080/19420889.2015.1034400

Cited by 4 publications

(3 citation statements)

References 18 publications

(31 reference statements)

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“…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.…”

Section: Functionmentioning

confidence: 99%

Intersectin scaffold proteins and their role in cell signaling and endocytosis

Herrero-Garcia

O’Bryan

2017

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Intersectins (ITSNs) are a family of multi-domain proteins involved in regulation of diverse cellular pathways. These scaffold proteins are well known for regulating endocytosis but also play important roles in cell signaling pathways including kinase regulation and Ras activation. ITSNs participate in several human cancers, such as neuroblastomas and glioblastomas, while its downregulation is associated with lung injury. Alterations in ITSN expression have been found in neurodegenerative diseases such as Down Syndrome and Alzheimer’s disease. Binding proteins for ITSNs include endocytic regulatory factors, cytoskeleton related proteins (i.e. actin or dynamin), signaling proteins as well as herpes virus proteins. This review will summarize recent studies on ITSNs, highlighting the importance of these scaffold proteins in the aforementioned processes.

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Section: Functionmentioning

confidence: 99%

Intersectin scaffold proteins and their role in cell signaling and endocytosis

Herrero-Garcia

O’Bryan

2017

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…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.…”

Section: Introductionmentioning

confidence: 99%

“…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 ].…”

Section: Introductionmentioning

confidence: 99%

Intersectin-1s deficiency in pulmonary pathogenesis

Jeganathan

Predescu

2017

Respir Res

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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 EHITSN and SH3A-EITSN fragments. The EHITSN 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 EHITSN 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.

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Intersectin goes nuclear: secret life of an endocytic protein

Alvisi

Paolini

Contarini

et al. 2018

Biochemical Journal

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Intersectin 1-short (ITSN1-s) is a 1220 amino acid ubiquitously expressed scaffold protein presenting a multidomain structure that allows to spatiotemporally regulate the functional interaction of a plethora of proteins. Besides its well-established role in endocytosis, ITSN1-s is involved in the regulation of cell signaling and is implicated in tumorigenesis processes, although the signaling pathways involved are still poorly understood. Here, we identify ITSN1-s as a nucleocytoplasmic trafficking protein. We show that, by binding to importin (IMP)α, a small fraction of ITSN1-s localizes in the cell nucleus at the steady state, where it preferentially associates with the nuclear envelope and interacts with lamin A/C. However, upon pharmacological ablation of chromosome region maintenance 1 (CRM-1)-dependent nuclear export pathway, the protein accumulates into the nucleus, thus revealing its moonlighting nature. Analysis of deletion mutants revealed that the coiled coil (CC) and Src homology (SH3) regions play the major role in its nucleocytoplasmic shuttling. While no evidence of nuclear localization signal (NLS) was detected in the CC region, a functional bipartite NLS was identified within the SH3D region of ITSN1-s (RKKNPGGWWEGELQARGKKRQIGW-1127), capable of conferring energy-dependent nuclear accumulation to reporter proteins and whose mutational ablation affects nuclear import of the whole SH3 region. Thus, ITSN1-s is an endocytic protein, which shuttles between the nucleus and the cytoplasm in a CRM-1- and IMPα-dependent fashion.

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New insights into the functions of intersectin-1s

Cited by 4 publications

References 18 publications

Intersectin scaffold proteins and their role in cell signaling and endocytosis

Intersectin scaffold proteins and their role in cell signaling and endocytosis

Intersectin-1s deficiency in pulmonary pathogenesis

Intersectin goes nuclear: secret life of an endocytic protein

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