Emerging Roles of Ruk/CIN85 in Vesicle-Mediated Transport, Adhesion, Migration and Malignancy

Havrylov, Serhiy; Redowicz, Maria Jolanta; Buchman, Vladimir L.

doi:10.1111/j.1600-0854.2010.01061.x

Cited by 56 publications

(81 citation statements)

References 87 publications

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“…This observation suggests that the acceleration of the kinetics of Fc⑀RI internalization due to the abundance of CIN85 perturbs intracellular signaling and leads to an inappropriate activation of mastocytes. The role of CIN85 in the attenuation of the immune response can be extended to additional immunoreceptors, such as the TCR or TNF receptor 1 (48). Coupled to its role in the down-regulation of receptor activation or of other proteins like Syk (63), CIN85 appears to play a central role in the coordination between intracellular signaling, down-regulation pathways, and sorting downstream of receptor engagement (48).…”

Section: Discussionmentioning

confidence: 99%

“…The role of CIN85 in the attenuation of the immune response can be extended to additional immunoreceptors, such as the TCR or TNF receptor 1 (48). Coupled to its role in the down-regulation of receptor activation or of other proteins like Syk (63), CIN85 appears to play a central role in the coordination between intracellular signaling, down-regulation pathways, and sorting downstream of receptor engagement (48). These functions of CIN85, in the particular context of the immune response, highlight the importance of adaptor proteins in the activation and regulation of cell functions dependent on receptor activation.…”

Section: Discussionmentioning

confidence: 99%

“…CIN85 does not possess any tyrosine phosphorylation sites but has potential sites of serine/threonine phosphorylation (47). However, these protein modifications on CIN85 are poorly documented in the literature (48). We examined whether this posttranslational modification of CIN85 could be detected in stimulated human neutrophils.…”

Section: Translocation Of Cin85 To Drm-hs Of the Plasma Membranes Folmentioning

confidence: 99%

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CIN85 Modulates the Down-regulation of FcγRIIa Expression and Function by c-Cbl in a PKC-dependent Manner in Human Neutrophils

Marois¹,

Vaillancourt

Paré

et al. 2011

Journal of Biological Chemistry

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We previously described a non-classical mechanism that arrests Fc␥RIIa signaling in human neutrophils once engaged by immune complexes or opsonized pathogens. The engagement of Fc␥RIIa leads to its ubiquitination by the ubiquitin ligase c-Cbl and degradation by the proteasome. Herein, we further examined some of the events regulating this novel pathway. The adaptor protein CIN85 was described in other systems to be involved in the regulation of the c-Cbl-dependent pathway. We found that CIN85 is expressed in human neutrophils and that it translocates like c-Cbl from the cytosol to the plasma membrane following receptor cross-linking. CIN85 was also recruited to the same subset of high density detergent-resistant membrane fractions in which stimulated Fc␥RIIa partitioned with c-Cbl. The integrity of these microdomains is essential to the Fc␥RIIa degradation process because the cholesterol-depleting agent methyl-␤-cyclodextrin inhibits this event. Silencing the expression of CIN85 by siRNA in dibutyryl cyclic AMP-differentiated PLB 985 cells prevented Fc␥RIIa degradation and increased IgG-mediated phagocytosis. Confocal microscopy revealed that the presence of CIN85 is essential to the proper sorting of Fc␥RIIa during endocytosis. We also provide direct evidence that CIN85 is a substrate of serine/threonine kinase PKCs. Classical PKCs positively regulate Fc␥RIIa ubiquitination and degradation because these events were inhibited by Gö6976, a classical PKC inhibitor. We conclude that the ubiquitination and degradation of stimulated Fc␥RIIa mediated by c-Cbl are positively regulated by the adaptor protein CIN85 in a PKC-dependent manner and that these events contribute to the termination of Fc␥RIIa signaling. Fc␥ receptors (Fc␥Rs)3 represent a family of membrane proteins involved in the recognition of the Fc portion of immunoglobulin G. They act as sensors for opsonized pathogens or immune complexes, and their engagement initiates intracellular signals that lead to multiple cell functions, such as degranulation, activation of the respiratory burst, and phagocytosis (1-3). Fc␥R isoforms either express an immunoreceptor tyrosine-based activating motif (ITAM) in their intracellular portion or associate with ITAM-containing accessory proteins with the exception of Fc␥RIIb, the unique inhibitory member of the Fc␥R family that transmits inhibitory signals through an immunoreceptor tyrosine-based inhibition motif (ITIM) (4, 5). In the case of antibody-mediated responses, such as IgG-dependent phagocytosis, neutrophils and other immune effectors, such as macrophages, have the capacity to trigger strong proinflammatory responses, which must be tightly controlled. On human neutrophils, only two Fc␥Rs, namely Fc␥RIIa (CD32a) and Fc␥RIIIb (CD16b), are constitutively expressed, neither of which possess an ITIM. The available data indicate that in contrast to other human phagocytes, including macrophages, human neutrophils express very little (6) or no (7) Fc␥RIIb.Several lines of evidence indicate that Fc␥RIIa is directly involve...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Translocation Of Cin85 To Drm-hs Of the Plasma Membranes Folmentioning

confidence: 99%

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CIN85 Modulates the Down-regulation of FcγRIIa Expression and Function by c-Cbl in a PKC-dependent Manner in Human Neutrophils

Marois¹,

Vaillancourt

Paré

et al. 2011

Journal of Biological Chemistry

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“…Among the various SH3 domains tested, only the three SH3 domains of CIN85 were able to retain SEPT9 from cell extracts on a glutathione-S-transferase (GST) affinity matrix. CIN85 is an adaptor protein implicated in various steps of the vesicular transport of EGFRs, including internalization, degradation and recycling (Havrylov et al, 2010), and we thus considered CIN85 as a candidate factor linking SEPT9 to EGFR sorting. We probed for a potential interaction and found a substantial fraction of endogenous SEPT9 to be co-immunoprecipitated with native CIN85 from cell extracts (Fig.…”

Section: Sept9 Controls Egfr Degradationmentioning

confidence: 99%

Septin 9 negatively regulates ubiquitin-dependent downregulation of epidermal growth factor receptor

Diesenberg

Beerbaum

Fink

et al. 2014

Journal of Cell Science

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Septins constitute a family of GTP-binding proteins that are involved in a variety of biological processes. Several isoforms have been implicated in disease, but the molecular mechanisms underlying pathogenesis are poorly understood. Here, we show that depletion of SEPT9 decreases surface levels of epidermal growth factor receptors (EGFRs) by enhancing receptor degradation. We identify a consensus motif within the SEPT9 N-terminal domain that supports its association with the adaptor protein CIN85 (also known as SH3KBP1). We further show CIN85-SEPT9 to be localized exclusively to the plasma membrane, where SEPT9 is recruited to EGF-engaged receptors in a CIN85-dependent manner. Finally, we demonstrate that SEPT9 negatively regulates EGFR degradation by preventing the association of the ubiquitin ligase Cbl with CIN85, resulting in reduced EGFR ubiquitylation. Taken together, these data provide a mechanistic explanation of how SEPT9, though acting exclusively at the plasma membrane, impairs the sorting of EGFRs into the degradative pathway.

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“…T he adaptor molecules CD2-associated protein (CD2AP) and Cbl-interacting protein of 85 kDa (CIN85) belong to a ubiquitously expressed protein family of adaptor molecules that are involved in a variety of cellular processes, like cell signaling (12,18,52), cytoskeletal arrangement (2,16,29,50), and degradative trafficking and endocytosis of receptors (15,24,26,43,45,49,57). The two proteins show high sequence and structural similarities, and they both contain three SH3 domains, a proline-rich region, and a coiled-coil domain (7).…”

mentioning

confidence: 99%

CD2AP Regulates SUMOylation of CIN85 in Podocytes

Tossidou

Niedenthal²,

Klaus³

et al. 2012

Molecular and Cellular Biology

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dPodocytes are highly differentiated and polarized epithelial cells located on the visceral side of the glomerulus. They form an indispensable component of the glomerular filter, the slit diaphragm, formed by several transmembrane proteins and adaptor molecules. Disruption of the slit diaphragm can lead to massive proteinuria and nephrotic syndrome in mice and humans. CD2AP is an adaptor protein that is important for the maintenance of the slit diaphragm. Together with its paralogue, CIN85, CD2AP belongs to a family of adaptor proteins that are primarily described as being involved in endocytosis and downregulation of receptor tyrosine kinase activity. We have shown that full-length CIN85 is upregulated in podocytes in the absence of CD2AP, whereas in wild-type cells, full-length CIN85 is not detectable. In this study, we show that full-length CIN85 is postranslationally modified by SUMOylation in wild-type podocytes. We can demonstrate that CIN85 is SUMOylated by SUMO-1, -2, and -3 and that SUMOylation is enhanced in the presence of CD2AP. Conversion of lysine 598 to arginine completely abolishes SUMOylation and leads to increased binding of CIN85 to nephrin. Our results indicate a novel role for CD2AP in regulating posttranslational modification of CIN85.T he adaptor molecules CD2-associated protein (CD2AP) and Cbl-interacting protein of 85 kDa (CIN85) belong to a ubiquitously expressed protein family of adaptor molecules that are involved in a variety of cellular processes, like cell signaling (12, 18, 52), cytoskeletal arrangement (2, 16, 29, 50), and degradative trafficking and endocytosis of receptors (15,24,26,43,45,49,57). The two proteins show high sequence and structural similarities, and they both contain three SH3 domains, a proline-rich region, and a coiled-coil domain (7). However, they appear to have completely different functional roles. While CD2AP is solely expressed in its full-length form, multiple CIN85/Ruk isoforms were identified in various tissues and cell lines, due to alternative splicing and different promoters (3,31).In podocytes CD2AP is expressed at the slit diaphragm, a specialized intercellular junction between neighboring podocytes covering the outer surface of the glomerular tuft. CD2AP interacts with several proteins at the slit diaphragm. One of the major components is nephrin, a transmembrane adhesion protein of the Ig superfamily. Humans and mice lacking nephrin are born without intact slit diaphragms and develop massive proteinuria in utero (22,40). Mice deficient in CD2AP are born healthy but develop a rapid-onset nephrotic syndrome at 3 weeks of age and die of renal failure 6 weeks after birth (44). We have previously demonstrated that deficiency of CD2AP leads to a differentiation-dependent increase of full-length CIN85 expression, which correlates with a loss of expression of the slit diaphragm protein nephrin in podocytes. Furthermore, we found that CIN85 is a binding partner of nephrin and that overexpression of CIN85 leads to increased endocytosis of nephrin after gr...

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Emerging Roles of Ruk/CIN85 in Vesicle-Mediated Transport, Adhesion, Migration and Malignancy

Cited by 56 publications

References 87 publications

CIN85 Modulates the Down-regulation of FcγRIIa Expression and Function by c-Cbl in a PKC-dependent Manner in Human Neutrophils

CIN85 Modulates the Down-regulation of FcγRIIa Expression and Function by c-Cbl in a PKC-dependent Manner in Human Neutrophils

Septin 9 negatively regulates ubiquitin-dependent downregulation of epidermal growth factor receptor

CD2AP Regulates SUMOylation of CIN85 in Podocytes

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