Characterization of the CIN85 Adaptor Protein and Identification of Components Involved in CIN85 Complexes

Watanabe, Shinji; Take, Hitoshi; Takeda, Kazuyo; Yu, Zu‐Xi; Iwata, Nobuhisa; Kajigaya, Sachiko

doi:10.1006/bbrc.2000.3760

Cited by 80 publications

(104 citation statements)

References 27 publications

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“…Overexpression of CIN85 or the closely related protein CMS/CD2AP has been reported to lead to the formation of multiple punctate structures in COS-7 cells, which contain several markers of the endosomal compartment [2,[23][24][25]. Similar multiple punctate structures were observed in CHO cells upon overexpression of CIN85 (Fig.…”

Section: Resultssupporting

confidence: 60%

Identification and characterization of a novel Rho GTPase activating protein implicated in receptor-mediated endocytosis

SAKAKIBARA¹

2004

FEBS Letters

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Cbl-interacting protein of 85 kDa (CIN85) is a recently identified adaptor protein involved in the endocytic process of several receptor tyrosine kinases. Here we have identified a novel RhoGAP, CIN85 associated multi-domain containing RhoGAP1 (CAMGAP1) as a binding protein for CIN85. CAMGAP1 is composed of an Src homology 3 (SH3) domain, multiple WW domains, a proline-rich region, a PH domain and a RhoGAP domain, and has the domain architecture similar to ARHGAP9 and ARHGAP12. CAMGAP1 mRNA is widely distributed in murine tissues. Biochemical assays showed its GAP activity toward Rac1 and Cdc42. Protein binding and expression studies indicated that the second SH3 domain of CIN85 binds to a proline-rich region of CAMGAP1. Overexpression of a truncated form of CAMGAP1 interferes with the internalization of transferrin receptors, suggesting that CAM-GAP1 may play a role in clathrin-mediated endocytosis.

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Section: Resultssupporting

confidence: 60%

Identification and characterization of a novel Rho GTPase activating protein implicated in receptor-mediated endocytosis

SAKAKIBARA¹

2004

FEBS Letters

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“…When we performed extended time course experiments growth factorinducible reduction of Grb2-SOS and inducible Grb2-CIN85 binding was also detectable in wild-type cells, but at later time points. Interestingly, Grb2 was identified earlier in association with CIN85 complexes in other cells; however, a time-dependent dynamic of this interaction was not previously described (23). In other epithelial cells, CIN85 is a well known mediator of ligand-dependent ubiquitination and down-regulation of RTKs (12,24,25), and is also described as a regulator of MEKK activity (26).…”

Section: Grb2-sos Binding Is Reduced In Cd2apmentioning

confidence: 95%

CD2AP/CIN85 Balance Determines Receptor Tyrosine Kinase Signaling Response in Podocytes

Tossidou¹,

Kardinal

Peters³

et al. 2007

Journal of Biological Chemistry

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Defects in podocyte signaling are the basis of many inherited glomerular diseases leading to glomerulosclerosis. CD2-associated protein (CD2AP) is highly expressed in podocytes and is considered to play an important role in the maintenance of the glomerular slit diaphragm. Mice deficient for CD2AP (CD2AP ؊/؊ ) appear normal at birth but develop a rapid onset nephrotic syndrome at 3 weeks of age. We demonstrate that impaired intracellular signaling with subsequent podocyte damage is the reason for this delayed podocyte injury in CD2AP ؊/؊ mice. We document that CD2AP deficiency in podocytes leads to diminished signal initiation and termination of signaling pathways mediated by receptor tyrosine kinases (RTKs). In addition, we demonstrate that CIN85, a paralog of CD2AP, is involved in termination of RTK signaling in podocytes. CIN85 protein expression is increased in CD2AP ؊/؊ podocytes in vitro. Stimulation of CD2AP؊/؊ podocytes with various growth factors, including insulin-like growth factor 1, vascular endothelial growth factor, and fibroblast growth factor, resulted in a significantly decreased phosphatidylinositol 3-kinase/AKT and ERK signaling response. Moreover, increased CIN85 protein is detectable in podocytes in diseased CD2AP ؊/؊ mice, leading to decreased base-line activation of ERK and decreased phosphorylation after growth factor stimulation in vivo. Because repression of CIN85 protein leads to a restored RTK signaling response, our results support an important role of CD2AP/ CIN85 protein balance in the normal signaling response of podocytes. Phosphatidylinositol 3-kinase (PI3K)2 and Ras/ERK mitogen-activated protein kinase signaling pathways are key factors for determining the specificity of cellular responses, including cell proliferation, cell differentiation, and cell survival (1, 2). We and others have previously demonstrated that the PI3K/AKT signaling response plays an important role for podocyte survival in particular in the presence of active transforming growth factor ␤ (3, 4). We recently demonstrated that the PI3K/AKT response is directly targeted by cytokine cross-talk and subsequently influences the cellular outcome (5). The adaptor molecules CD2-associated protein (CD2AP) and CIN85 belong to a family of adaptor molecules that selectively control the spatial and temporal assembly of multiprotein complexes that transmit intracellular signals. For both molecules various interaction partners have been described placing them at the center of regulatory pathways involving signaling (6, 7), cytoskeletal arrangement (8, 9), vesicular trafficking (10), and endocytosis (11,12). In this study we demonstrate that CD2AP and CIN85 contribute to the balance of RTK signaling in podocytes. The anatomical localization of the podocyte exposes this highly specialized cell type to a variety of cellular stressors like stretch force, reactive oxygen species, osmotic milieu changes, cytokines and chemokines, filtrated toxins, and waste products. Therefore, this location requires the cells to have a highly e...

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“…The protein is a homo-oligomer, an association driven by a coiled-coil (leucine-zipper) domain at the extreme C terminus. 8 The amino terminus consists of three Src homology 3 (SH3) domains (SH3A, -B, and -C) separated by intervening sequences of undetermined structure. SH3 domains are found in various proteins, where they exert their typical function: molecular recognition and subsequent binding.…”

mentioning

confidence: 99%

Structure of the Kidney Slit Diaphragm Adapter Protein CD2-Associated Protein as Determined with Electron Microscopy

Adair

Altintas

Möller

et al. 2014

Journal of the American Society of Nephrology

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CD2-associated protein (CD2AP) is a multidomain scaffolding protein that has a critical role in renal function. CD2AP is expressed in glomerular podocytes at the slit diaphragm, a modified adherens junction that comprises the protein filtration barrier of the kidney, and interacts with a number of protein ligands involved in cytoskeletal remodeling, membrane trafficking, cell motility, and cell survival. The structure of CD2AP is unknown. We used electron microscopy and single particle image analysis to determine the threedimensional structure of recombinant full-length CD2AP and found that the protein is a tetramer in solution. Image reconstruction of negatively stained protein particles generated a structure at 21 Å resolution. The protein assumed a roughly spherical, very loosely packed structure. Analysis of the electron density map revealed that CD2AP consists of a central coiled-coil domain, which forms the tetramer interface, surrounded by four symmetry-related motifs, each containing three globular domains corresponding to the three SH3 domains. The spatial organization exposes the binding sites of all 12 SH3 domains in the tetramer, allowing simultaneous binding to multiple targets. Determination of the structure of CD2AP provides novel insights into the biology of this slit diaphragm protein and lays the groundwork for characterizing the interactions between key molecules of the slit diaphragm that control glomerular filtration.

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Characterization of the CIN85 Adaptor Protein and Identification of Components Involved in CIN85 Complexes

Cited by 80 publications

References 27 publications

Identification and characterization of a novel Rho GTPase activating protein implicated in receptor-mediated endocytosis

Identification and characterization of a novel Rho GTPase activating protein implicated in receptor-mediated endocytosis

CD2AP/CIN85 Balance Determines Receptor Tyrosine Kinase Signaling Response in Podocytes

Structure of the Kidney Slit Diaphragm Adapter Protein CD2-Associated Protein as Determined with Electron Microscopy

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