Felic (CIP4b), a novel binding partner with the Src kinase Lyn and Cdc42, localizes to the phagocytic cup

Dombrosky-Ferlan, Patrice; Grishin, Anatoly; Botelho, Roberto J.; Sampson, Matthew G.; Wang, Lin; Rudert, William A.; Grinstein, Sergio; Corey, Seth J.

doi:10.1182/blood-2002-03-0851

Cited by 34 publications

(29 citation statements)

References 37 publications

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“…The prolonged surface exposure of the receptor, furthermore, was associated with an increase in the kinase activity of the receptor, which was transmitted into a higher migratory ability of cells in which the CIP4-like proteins were ablated with siRNA techniques. An involvement of CIP4 in cell migration was suggested by the observation that overexpression of CIP4 decreases the fibroblast migration in wound healing and Matrigel invasion assays (Dombrosky-Ferlan et al, 2003). Our results show the reciprocal effect: knock-down of the CIP4-like proteins resulted in an increased PDGF-induced cell migration, and it also demonstrated a more direct involvement of the CIP4-like proteins in cell migration.…”

Section: Discussionsupporting

confidence: 58%

Members of the CIP4 family of proteins participate in the regulation of platelet‐derived growth factor receptor‐β‐dependent actin reorganization and migration

Toguchi¹,

Richnau²,

Ruusala³

et al. 2010

Biology of the Cell

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Background information. The F-BAR {Fes/CIP4 [Cdc42 (cell division cycle 42)-interacting protein 4] homology and BAR (Bin/amphiphysin/Rvs)} proteins have emerged as important co-ordinators of signalling pathways that regulate actin assembly and membrane dynamics. The presence of the F-BAR domain is the hallmark of this family of proteins and the CIP4 (Cdc42-interacting protein 4) was one of the first identified vertebrate F-BAR proteins. There are three human CIP4 paralogues, namely CIP4, FBP17 (formin-binding protein 17) and Toca-1 (transducer of Cdc42-dependent actin assembly 1). The CIP4-like proteins have been implicated in Cdc42-dependent actin reorganization and in regulation of membrane deformation events visible as tubulation of lipid bilayers.Results. We performed side-by-side analyses of the three CIP4 paralogues. We found that the three CIP4-like proteins vary in their effectiveness to catalyse membrane tubulation and actin reorganization. Moreover, we show that the CIP4-dependent membrane tubulation is enhanced in the presence of activated Cdc42. Some F-BAR members have been shown to have a role in the endocytosis of the EGF (epidermal growth factor) receptor and this prompted us to study the involvement of the CIP4-like proteins in signalling of the PDGFRβ [PDGF (platelet-derived growth factor) β-receptor]. We found that knock-down of CIP4-like proteins resulted in a prolonged formation of PDGF-induced dorsal ruffles, as well as an increased PDGF-dependent cell migration. This was most likely a consequence of a sustained PDGFRβ activation caused by delayed internalization of the receptor in the cells treated with siRNA (small interfering RNA) specific for the CIP4-like proteins.Conclusions. Our findings show that CIP4-like proteins induced membrane tubulation downstream of Cdc42 and that they have important roles in PDGF-dependent actin reorganization and cell migration by regulating internalization and activity of the PDGFRβ. Moreover, the results suggest an important role for the CIP4-like proteins in the regulation of the activity of the PDGFRβ.

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Section: Discussionsupporting

confidence: 58%

Members of the CIP4 family of proteins participate in the regulation of platelet‐derived growth factor receptor‐β‐dependent actin reorganization and migration

Toguchi¹,

Richnau²,

Ruusala³

et al. 2010

Biology of the Cell

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“…Although CIP4 was identified as a potential Src substrate (Lock et al, 1998;Dombrosky-Ferlan et al, 2003), the potential involvement of CIP4 in Src signaling in breast tumor cells has not been reported. To test this, MDA-MB-231 cells were transduced with either a control retrovirus (MDA-vec) or a retrovirus expressing activated Src-Y527F (MDA-SrcYF).…”

Section: Cip4 Is Part Of the Src Signaling Axis In Breast Tumor Cellsmentioning

confidence: 99%

“…Because Y471 in CIP4 was previously reported to be a potential Src phosphorylation site (Dombrosky-Ferlan et al, 2003), we prepared a Y471F mutation in a GFP-CIP4 expression plasmid, and performed co-transfections of GFP-CIP4 with or without SrcYF plasmid in HEK293 cells. As expected, SrcYF expression induced robust tyrosine phosphorylation of CIP4 (Fig.…”

Section: Src Phosphorylates Cip4 On Y471 Leading To Altered Cip4 Funmentioning

confidence: 99%

“…CIP4 (also known as TRIP10) is an adaptor protein that was identified as a potential Src SH3-domain binding partner and substrate (Lock et al, 1998;Dombrosky-Ferlan et al, 2003). CIP4 also interacts with known regulators of invadopodia, including Cdc42 (Aspenstrom, 1997), N-WASP (Tian et al, 2000), dynamin (Itoh et al, 2005), and Diaphanous-related formins (Aspenstrom et al, 2006a).…”

Section: Introductionmentioning

confidence: 99%

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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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“…CIP4 was first identified using the activated form of Cdc42 or the non-catalytic domains of the Src kinase Lyn as bait in yeast two-hybrid screens (12,13). An alternate splice form (CIP4h or CIP4/2) was discovered in a PCR screen (14) and in a yeast two-hybrid of 3T3L1 cells with the RhoGTPase Tc10 as bait (15).…”

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confidence: 99%

The Cdc42-interacting Protein-4 (CIP4) Gene Knock-out Mouse Reveals Delayed and Decreased Endocytosis

Feng

Hartig

Bechill

et al. 2010

Journal of Biological Chemistry

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The newly described F-BAR (Fer/CIP4 and Bin, amphiphysin, Rvs) family of proteins includes Cdc42-interacting protein-4 (CIP4), formin-binding protein-17 (FBP-17) and transactivator of cytoskeletal assembly-1 (Toca-1), and drives membrane deformation and invagination. Membrane remodeling affects endocytosis, vesicle budding, and cargo selection. The F-BAR family presents a novel family of proteins, which little is known about their in vivo function. We investigated the physiological role of CIP4, by creating Cip4-null mice through homologous recombination. Compared with their wild-type littermates, the Cip4-null mice displayed lower early post-prandial glucose levels. Adipocytes isolated from Cip4-null mice exhibited increased [ 14 C]2-deoxyglucose uptake compared with cells from wild-type mice. The enhanced insulin sensitivity was not due to higher levels of insulin or phospho-Akt, a critical player in insulin signaling. However, higher glucose transporter 4 (GLUT4) levels were detected in muscle membrane fractions in Cip4-null mice under insulin stimulation. Mouse embryonic fibroblasts from Cip4-null mice demonstrated decreased transferrin uptake, fluorescein isothiocyanate-dextran, and horseradish peroxidase uptake, indicating that CIP4 affects multiple modes of endocytosis. These studies demonstrate a physiological role for CIP4 in endocytosis leading to a whole animal phenotype.

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Felic (CIP4b), a novel binding partner with the Src kinase Lyn and Cdc42, localizes to the phagocytic cup

Cited by 34 publications

References 37 publications

Members of the CIP4 family of proteins participate in the regulation of platelet‐derived growth factor receptor‐β‐dependent actin reorganization and migration

Members of the CIP4 family of proteins participate in the regulation of platelet‐derived growth factor receptor‐β‐dependent actin reorganization and migration

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

The Cdc42-interacting Protein-4 (CIP4) Gene Knock-out Mouse Reveals Delayed and Decreased Endocytosis

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