Cdc42 interacting protein 4 (CIP4) is essential for integrin-dependent T-cell trafficking

Suresh, K.; Kumar, Lalit; Massaad, Michel J.; Ramesh, Narayanaswamy; Bras, Séverine Le; Özcan, Esra; Oyoshi, Michiko K.; Kaku, Mayumi; Fujiwara, Yuko; Kremer, Leonor; King, Sandra L.; Fuhlbrigge, Robert C.; Rodig, Scott J.; Sage, Peter T.; Carman, Christopher V.; Alcaide, Pilar; Luscinskas, Francis W.; Geha, Raif S.

doi:10.1073/pnas.1002747107

Cited by 22 publications

(24 citation statements)

References 30 publications

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“…This is consistent with cell-based studies implicating CIP4 in regulating both the trafficking of GLUT4 storage vesicles to the plasma membrane (Lodhi et al, 2007), as well as GLUT4 endocytosis via CIP4 interactions with N-WASP and dynamin-2 (Hartig et al, 2009). CIP4 has also been implicated in positioning of the microtubule-organizing center for directed exocytosis of cytolytic granules in natural killer (NK) cells (Banerjee et al, 2007), although a recent study of CIP4-knockout mice showed normal NK cell function (Koduru et al, 2010). However, this study also shows that CIP4 promotes integrinmediated recruitment of effector T cells to sites of cutaneous inflammation (Koduru et al, 2010).…”

Section: Introductioncontrasting

confidence: 40%

“…CIP4 has also been implicated in positioning of the microtubule-organizing center for directed exocytosis of cytolytic granules in natural killer (NK) cells (Banerjee et al, 2007), although a recent study of CIP4-knockout mice showed normal NK cell function (Koduru et al, 2010). However, this study also shows that CIP4 promotes integrinmediated recruitment of effector T cells to sites of cutaneous inflammation (Koduru et al, 2010). CIP4 also functions in endosome to lysosome trafficking of EGFR (Hu et al, 2009).…”

Section: Introductionmentioning

confidence: 43%

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Cdc42-interacting protein 4 is a Src substrate that regulates invadopodia and invasiveness of breast tumors by promoting MT1-MMP endocytosis

Mukhopadhyay

Truesdell

et al. 2011

Journal of Cell Science

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SummaryInvadopodia are actin-rich membrane protrusions that promote extracellular matrix degradation and invasiveness of tumor cells. Src protein-tyrosine kinase is a potent inducer of invadopodia and tumor metastases. Cdc42-interacting protein 4 (CIP4) adaptor protein interacts with actin regulatory proteins and regulates endocytosis. Here, we show that CIP4 is a Src substrate that localizes to invadopodia in MDA-MB-231 breast tumor cells expressing activated Src (MDA-SrcYF). To probe the function of CIP4 in invadopodia, we established stable CIP4 knockdown in MDA-SrcYF cell lines by RNA interference. Compared with control cells, CIP4 knockdown cells degrade more extracellular matrix (ECM), have increased numbers of mature invadopodia and are more invasive through matrigel. Similar results are observed with knockdown of CIP4 in EGF-treated MDA-MB-231 cells. This inhibitory role of CIP4 is explained by our finding that CIP4 limits surface expression of transmembrane type I matrix metalloprotease (MT1-MMP), by promoting MT1-MMP internalization. Ectopic expression of CIP4 reduces ECM digestion by MDA-SrcYF cells, and this activity is enhanced by mutation of the major Src phosphorylation site in CIP4 (Y471). Overall, our results identify CIP4 as a suppressor of Srcinduced invadopodia and invasion in breast tumor cells by promoting endocytosis of MT1-MMP.

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Section: Introductioncontrasting

confidence: 40%

Section: Introductionmentioning

confidence: 43%

Cdc42-interacting protein 4 is a Src substrate that regulates invadopodia and invasiveness of breast tumors by promoting MT1-MMP endocytosis

Mukhopadhyay

Truesdell

et al. 2011

Journal of Cell Science

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“…B cells from CIP4 KO mice proliferate and class switch normally in vitro in response to LPS, anti-CD40, and antiIgM Abs. However, GC formation and the humoral immune response are reduced in these mice, which also exhibit a T cell migration deficiency (26). Additional experiments are needed to determine the function of CIP4 and other F-bar proteins in B cells.…”

Section: Discussionmentioning

confidence: 99%

“…The CD23-cre mice were a gift of M. Busslinger (Vienna Biocenter) (25). CIP4 2/2 mice have been described previously (26). All strains were on a C57BL/6 background.…”

Section: Mice and Immunizationsmentioning

confidence: 99%

The Rho GTPase Cdc42 Is Essential for the Activation and Function of Mature B Cells

Gerasimčik

Dahlberg

Baptista

et al. 2015

The Journal of Immunology

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The Rho GTPase Cdc42 coordinates regulation of the actin and the microtubule cytoskeleton by binding and activating the Wiskott–Aldrich syndrome protein. We sought to define the role of intrinsic expression of Cdc42 by mature B cells in their activation and function. Mice with inducible deletion of Cdc42 in mature B cells formed smaller germinal centers and had a reduced Ab response, mostly of low affinity to T cell–dependent Ag, compared with wild-type (WT) controls. Spreading formation of long protrusions that contain F-actin, microtubules, and Cdc42-interacting protein 4, and assumption of a dendritic cell morphology in response to anti-CD40 plus IL-4 were impaired in Cdc42-deficient B cells compared with WT B cells. Cdc42-deficient B cells had an intact migratory response to chemokine in vitro, but their homing to the B cell follicles in the spleen in vivo was significantly impaired. Cdc42-deficient B cells induced a skewed cytokine response in CD4+ T cells, compared with WT B cells. Our results demonstrate a critical role for Cdc42 in the motility of mature B cells, their cognate interaction with T cells, and their differentiation into Ab-producing cells.

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“…Although CIP4 contributes to T-cell adhesion and migration 49 and to NK cell cytotoxicity, 29 we have not observed in CIP4 mice such a profound immunodeficiency that is similar to that of WAS-null mice. 50 WAS-null mice and CIP4-null mice also differ in regard to proplatelet and DMS formation in primary megakaryocytes.…”

Section: Discussionmentioning

confidence: 73%

Loss of the F-BAR protein CIP4 reduces platelet production by impairing membrane-cytoskeleton remodeling

Chen

Aardema

Kale

et al. 2013

Blood

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Key Points• CIP4 affects the remodeling of both plasma membrane and cortical cytoskeleton in megakaryocytes.• CIP4 in platelet biogenesis involves cortical tension, as does WASP, and WASPindependent plasma membrane reorganization.Megakaryocytes generate platelets through extensive reorganization of the cytoskeleton and plasma membrane. Cdc42 interacting protein 4 (CIP4) is an F-BAR protein that localizes to membrane phospholipids through its BAR domain and interacts with WiskottAldrich Syndrome Protein (WASP) via its SRC homology 3 domain. F-BAR proteins promote actin polymerization and membrane tubulation. To study its function, we generated CIP4-null mice that displayed thrombocytopenia similar to that of WAS 2 mice.The number of megakaryocytes and their progenitors was not affected. However, the number of proplatelet protrusions was reduced in CIP4-null, but not WAS 2 , megakaryocytes. Electron micrographs of CIP4-null megakaryocytes showed an altered demarcation membrane system. Silencing of CIP4, not WASP, expression resulted in fewer proplatelet-like extensions. Fluorescence anisotropy studies showed that loss of CIP4 resulted in a more rigid membrane. Micropipette aspiration demonstrated decreased cortical actin tension in megakaryocytic cells with reduced CIP4 or WASP protein. These studies support a new biophysical mechanism for platelet biogenesis whereby CIP4 enhances the complex, dynamic reorganization of the plasma membrane (WASP independent) and actin cortex network (as known for WASP and cortical actin) to reduce the work required for generating proplatelets. CIP4 is a new component in the highly coordinated system of megakaryocytic membrane and cytoskeletal remodeling affecting platelet production. (Blood. 2013;122(10):1695-1706

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Cdc42 interacting protein 4 (CIP4) is essential for integrin-dependent T-cell trafficking

Cited by 22 publications

References 30 publications

Cdc42-interacting protein 4 is a Src substrate that regulates invadopodia and invasiveness of breast tumors by promoting MT1-MMP endocytosis

Cdc42-interacting protein 4 is a Src substrate that regulates invadopodia and invasiveness of breast tumors by promoting MT1-MMP endocytosis

The Rho GTPase Cdc42 Is Essential for the Activation and Function of Mature B Cells

Loss of the F-BAR protein CIP4 reduces platelet production by impairing membrane-cytoskeleton remodeling

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