Phosphorylation of human enhancer of filamentation (HEF1) on serine 369 induces its proteasomal degradation

Hivert, Virginie; Pierre, Josiane; Raingeaud, Joël

doi:10.1016/j.bcp.2009.06.005

Cited by 13 publications

(14 citation statements)

References 43 publications

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“…Y189 phosphorylation is implicated in focal adhesion; this is a proposed phosphorylation site for FAK and SRC kinases [114]. Phosphorylation of S296 by Aurora-A kinase is implicated in NEDD9 proteasomal degradation [115], cell spreading [116] and cell cycle control [30]. NEDD9 potentiates TGFβ signaling by recruiting the inhibitory SMAD6 and SMAD7 proteins, and preventing their interaction with TGFβ [63].…”

Section: Figurementioning

confidence: 99%

Preclinical and clinical studies of the NEDD9 scaffold protein in cancer and other diseases

Shagisultanova

Gaponova

Gabbasov

et al. 2015

Gene

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Cancer progression requires a significant reprogramming of cellular signaling to support the essential tumor-specific processes that include hyperproliferation, invasion (for solid tumors) and survival of metastatic colonies. NEDD9 (also known as CasL and HEF1) encodes a multi-domain scaffolding protein that assembles signaling complexes regulating multiple cellular processes relevant to cancer. These include responsiveness to signals emanating from the T and B cell receptors, integrins, chemokine receptors, and receptor tyrosine kinases, as well as cytoplasmic oncogenes such as BCR-ABL and FAK- and SRC-family kinases. Downstream, NEDD9 regulation of partners including CRKL, WAVE, PI3K/AKT, ERK, E-cadherin, Aurora-A (AURKA), HDAC6, and others allow NEDD9 to influence functions as pleiotropic as migration, invasion, survival, ciliary resorption, and mitosis. In this review, we summarize a growing body of preclinical and clinical data that indicate that while NEDD9 is itself non-oncogenic, changes in expression of NEDD9 (most commonly elevation of expression) are common features of tumors, and directly impact tumor aggressiveness, metastasis, and response to at least some targeted agents inhibiting NEDD9-interacting proteins. These data strongly support the relevance of further development of NEDD9 as a biomarker for therapeutic resistance. Finally, we briefly discuss emerging evidence supporting involvement of NEDD9 in additional pathological conditions, including stroke and polycystic kidney disease.

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Section: Figurementioning

confidence: 99%

Preclinical and clinical studies of the NEDD9 scaffold protein in cancer and other diseases

Shagisultanova

Gaponova

Gabbasov

et al. 2015

Gene

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“…Protein phosphatase 2A (PP2A) binds and dephosphorylates both BCAR1 [109] and NEDD9 [110, 111]. PP2A negatively regulates the mitotic phosphorylation of BCAR1 [109].…”

Section: Introductionmentioning

confidence: 99%

“…PP2A negatively regulates the mitotic phosphorylation of BCAR1 [109]. PP2A is required for the de-adhesion-induced conversion from p115 to p105 kDa NEDD9 [110], potentially by targeting the Ser369 phosphorylation associated with this conversion [111]. The PRL (phosphatases of regenerating liver) subfamily of kinases are also linked to positive regulation of tumor growth; overexpression of PRL-1 was found to reduce BCAR1 levels [112], but inhibition of PRL phosphatases with a small molecule, thienopyridone, lead to BCAR1 cleavage [113].…”

Section: Introductionmentioning

confidence: 99%

“…The more slowly migrating, p115 kDa, serine/threonine phosphorylated form of NEDD9 that accumulates in attached and in G2/M cells has been described as more susceptible to proteolytic degradation [110]. Conversion of p105 to p115 NEDD9 has been reported as triggered by a phosphorylation at aa S369 by a kinase inhibited by Hesperadin, with this phosphorylation promoting proteasomal degradation [111]. NEDD9 is also targeted for proteosomal degradation by induced TGF-β signaling [65, 66].…”

Section: Introductionmentioning

confidence: 99%

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CAS proteins in normal and pathological cell growth control

Tikhmyanova

Little

Golemis

2009

Cell. Mol. Life Sci.

175

248

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Proteins of the CAS (Crk-Associated Substrate) family (BCAR1/p130Cas, NEDD9/HEF1/Cas-L, EFS/SIN and CASS4/HEPL) are integral players in normal and pathological cell biology. CAS proteins act as scaffolds to regulate protein complexes controlling migration and chemotaxis, apoptosis, cell cycle, and differentiation, and have more recently been linked to a role in progenitor cell function. Reflecting these complex functions, over-expression of CAS proteins has now been strongly linked to poor prognosis and increased metastasis in cancer, as well as resistance to firstline chemotherapeutics in multiple tumor types including breast and lung cancers, glioblastoma, and melanoma. Further, CAS proteins have also been linked to additional pathological conditions including inflammatory disorders, Alzheimer's and Parkinson's disease, as well as developmental defects. This review will explore the roles of the CAS proteins in normal and pathological states in the context of the many mechanistic insights into CAS protein function that have emerged in the past decade.

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“…In addition to the tyrosines, we note conservation of serine (S) 369 NEDD9 in the p130Cas and HEPL human, mouse and rat sequences. Previous studies have shown that this residue is critical for NEDD9 targeting by the proteasome [19] and plays a role in NEDD9-mediated cell spreading [20]. Leucine (L) 751 of NEDD9 that mediates binding to BCAR3/AND34/NSP2 [21] is conserved in p130Cas and this site has recently been confirmed to mediate the same interaction for p130Cas [22].…”

Section: Discussionmentioning

confidence: 96%

Tyrosine Y189 in the Substrate Domain of the Adhesion Docking Protein NEDD9 Is Conserved with p130Cas Y253 and Regulates NEDD9-Mediated Migration and Focal Adhesion Dynamics

2013

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The focal adhesion docking protein NEDD9/HEF1/Cas-L regulates cell migration and cancer invasion. NEDD9 is a member of the Cas family of proteins that share conserved overall protein-protein interaction domain structure, including a substrate domain that is characterized by extensive tyrosine (Y) phosphorylation. Previous studies have suggested that phosphorylation of Y253 in the substrate domain of the Cas family protein p130Cas is specifically required for p130Cas function in cell migration. While it is clear that tyrosine phosphorylation of the NEDD9 substrate domain is similarly required for the regulation of cell motility, whether individual NEDD9 tyrosine residues have discrete function in regulating motility has not previously been reported. In the present study we have used a global sequence alignment of Cas family proteins to identify a putative NEDD9 equivalent of p130Cas Y253. We find that NEDD9 Y189 aligns with p130Cas Y253 and that it is conserved among NEDD9 vertebrate orthologues. Expression of NEDD9 in which Y189 is mutated to phenylalanine results in increased rates of cell migration and is correlated with increased disassembly of GFP.NEDD9 focal adhesions. Conversely, mutation to Y189D significantly inhibits cell migration. Our previous data has suggested that NEDD9 stabilizes focal adhesions and the present data therefore suggests that phosphorylation of Y189 NEDD9 is required for this function. These findings indicate that the individual tyrosine residues of the NEDD9 substrate domain may serve discrete functional roles. Given the important role of this protein in promoting cancer invasion, greater understanding of the function of the individual tyrosine residues is important for the future design of approaches to target NEDD9 to arrest cancer cell invasion.

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Phosphorylation of human enhancer of filamentation (HEF1) on serine 369 induces its proteasomal degradation

Cited by 13 publications

References 43 publications

Preclinical and clinical studies of the NEDD9 scaffold protein in cancer and other diseases

Preclinical and clinical studies of the NEDD9 scaffold protein in cancer and other diseases

CAS proteins in normal and pathological cell growth control

Tyrosine Y189 in the Substrate Domain of the Adhesion Docking Protein NEDD9 Is Conserved with p130Cas Y253 and Regulates NEDD9-Mediated Migration and Focal Adhesion Dynamics

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