PKCepsilon controls the traffic of beta1 integrins in motile cells

Ivaska, Johanna; Whelan, Richard D. H.; Watson, Rose; Parker, Peter J.

doi:10.1093/emboj/cdf371

Cited by 137 publications

(156 citation statements)

References 32 publications

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“…The PKC inhibitors that blocked claudin-4 phosphorylation also inhibited the effects of TPA on TJ barrier, again suggesting claudin-4 as an important target of PKCε for its TJ-related effects. PKCε contribution to cell motility has been linked to β1 integrin by regulating its trafficking [48]. It is also known to be associated with β1 integrin through RACK1 and F-actin in mediating cell adhesion and mobility [49,50].…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of claudin-4 by PKCε regulates tight junction barrier function in ovarian cancer cells

D’Souza

Indig

Morin

2007

Experimental Cell Research

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Claudin proteins belong to a large family of transmembrane proteins essential to the formation and maintenance of tight junctions (TJs). In ovarian cancer, TJ protein claudin-4 is frequently overexpressed and may have roles in survival and invasion, but the molecular mechanisms underlying its regulation are poorly understood. In this report, we show that claudin-4 can be phosphorylated by protein kinase C (PKC) at Thr189 and Ser194 in ovarian cancer cells and overexpression of a claudin-4 mutant protein mimicking the phosphorylated state results in the disruption of the barrier function. Furthermore, upon phorbol ester-mediated PKC activation of OVCA433 cells, TJ strength is decreased and claudin-4 localization is altered. Analyses using PKC inhibitors and siRNA suggest that PKCε, an isoform typically expressed in ovarian cancer cells, may be important in the TPAmediated claudin-4 phosphorylation and weakening of the TJs. Furthermore, immunofluorescence studies showed that claudin-4 and PKCε are co-localized at the TJs in these cells. The modulation of claudin-4 activity by PKCε may not only provide a mechanism for disrupting TJ function in ovarian cancer, but may also be important in the regulation of TJ function in normal epithelial cells.

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Section: Discussionmentioning

confidence: 99%

Phosphorylation of claudin-4 by PKCε regulates tight junction barrier function in ovarian cancer cells

D’Souza

Indig

Morin

2007

Experimental Cell Research

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“…The most compelling example comes from reports of the reciprocal regulation of PKCε and β1 integrin signaling. PKCε overexpression increased β1 integrin protein levels, augmented the open (active) conformation of β1 integrin [103] and increased recycling of β1 integrin to the cell surface [110]. Engagement of integrins can trigger signaling through the PI3K pathway [111,112].…”

Section: Pkcε: Akting In Concert To Promote Survivalmentioning

confidence: 99%

Protein kinase Cε makes the life and death decision

Basu

Sivaprasad

2007

Cellular Signalling

144

154

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Cancer is caused by dysregulation in cellular signaling systems that control cell proliferation, differentiation and cell death. Protein kinase C (PKC), a family of serine/threonine kinases, plays an important role in the growth factor signal transduction pathway. PKCε, however, is the only PKC isozyme that has been considered as an oncogene. It can contribute to malignancy by enhancing cell proliferation or by inhibiting cell death. This review focuses on how PKCε collaborates with other signaling pathways, such as Ras/Raf/ERK and Akt, to regulate cell survival and cell death. We have also discussed how PKCε mediates is antiapoptotic signal by altering the level or function of proand antiapoptotic Bcl-2 family members.

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“…SAOS-␣2␤1 cells were transfected with FuGENE reagent (Boehringer Mannheim, Indianapolis, IN) and the cells were used for experiments after an expression time of 25-40 h. The GFP constructs of actin (CLONTECH, Palo Alto, CA), caveolin-1 (caveolin-GFP; from Dr. Ari Helenius, Institute of Biochemistry, ETH-Hoenggerberg, Switzerland; Pelkmans et al, 2001) wild-type Eps15 (DIIId2; from Dr. Alice Dautry-Varsat, Pasteur Institute, Paris; Benmerah et al, 1998), dominant negative (DN) Eps15 (d95/925; from Dr. Alice Dautry-Varsat, Pasteur Institute, Paris; Benmerah et al, 1999), wild-type PKC␣ (Dr. Peter J. Parker, Cancer Research, UK; Ng et al, 1999b), DN PKC␣ (T497A kinase-dead, substrate-binding mutant; Dr. Peter J. Parker, Cancer Research, UK; Mostafavi-Pour et al, 2003), and DN PKC⑀ (kinase dead form; Ivaska et al, 2002b) were used. DN MEK (1E8; from Dr. Natalie Ahn, University of Colorado;Holmströ m et al, 1999), constitutively active MEK (1R4F; from Dr. Natalie Ahn, University of Colorado; Holmströ m et al, 1999), and DN Ras (asn-17-ras; from Dr. Larry Feig, Tufts University; Feig and Cooper, 1988) were cotransfected to the cells with pEGFP-C2 (CLONTECH).…”

Section: Transfectionsmentioning

confidence: 99%

Clustering Induces a Lateral Redistribution of α2β1 Integrin from Membrane Rafts to Caveolae and Subsequent Protein Kinase C-dependent Internalization

Upla

Marjomäki

Kankaanpää

et al. 2004

MBoC

151

186

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Integrin ␣2␤1 mediates the binding of several epithelial and mesenchymal cell types to collagen. The composition of the surrounding plasma membrane, especially caveolin-1-and cholesterol-containing membrane structures called caveolae, may be important to integrin signaling. On cell surface ␣2␤1 integrin was located in the raft like membrane domain, rich in GPI-anchored proteins, rather than in caveolae. However, when antibodies were used to generate clusters of ␣2␤1 integrin, they started to move laterally on cell surface along actin filaments. During the lateral movement small clusters fused together. Finally ␣2␤1 integrin was found inside caveolae and subsequently internalized into caveosome-like perinuclear structures. The internalization process, unlike cluster formation or lateral redistribution, was dependent on protein kinase C␣ activity. Caveolae are known to be highly immobile structures and ␣2␤1 integrin clusters represent a previously unknown mechanism to activate endocytic trafficking via caveolae. The process was specific to ␣2␤1 integrin, because the antibody-mediated formation of ␣V integrin clusters activated their internalization in coated vesicles and early endosomes. In addition to natural ligands human echovirus-1 (EV1) gains entry into the cell by binding to ␣2␤1 and taking advantage of ␣2␤1 internalization via caveolae. INTRODUCTIONCaveolae are cave-like invaginations of the cell surface (for reviews see Kurzchalia and Parton, 1999;Parton 2003). They have been described as highly immobile and not involved in constitutive endocytic trafficking (Thomsen et al., 2002). Their internalization can be activated, for example, by the phosphatase inhibitor okadaic acid (Parton et al., 1994). In endothelial cells the interaction of albumin docking protein gp60 and caveolin-1 initiates the endocytosis of caveolae (Minshall et al., 2000). Caveolins are membrane proteins that are molecular markers of caveolae and shown to be crucial for the formation of these structures (Fra et al., 1995). Caveolins can be associated with cell surface growth factor receptors (Couet et al., 1997) and cell adhesion receptors (Wary et al., 1996(Wary et al., , 1998Wei et al., 1999) and caveolae might therefore play a role in cellular signaling. In addition, caveolae have been suggested to participate in the uptake of folate by pinocytosis, but this is still under discussion (Parton, 2003). Caveolin-deficient mice have given novel insight into the function of caveolae. Caveolin-1 gene knockout leads to pulmonary defects, vasoconstriction, or dilatation abnormalities and resistance to diet-induced obesity (Drab et al., 2001;Razani et al., 2001;Schubert et al., 2001;Sotgia et al., 2002;Razani et al., 2002). Simian virus 40 (SV40) has been shown to be internalized through caveolae and detailed studies focused on the virus entry mechanism have produced a lot of new information about the biology of caveolae (Pelkmans et al., 2001. We have recently shown that human echovirus 1 (EV1) is another virus using caveolae in its entry (Mar...

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PKCepsilon controls the traffic of beta1 integrins in motile cells

Cited by 137 publications

References 32 publications

Phosphorylation of claudin-4 by PKCε regulates tight junction barrier function in ovarian cancer cells

Phosphorylation of claudin-4 by PKCε regulates tight junction barrier function in ovarian cancer cells

Protein kinase Cε makes the life and death decision

Clustering Induces a Lateral Redistribution of α2β1 Integrin from Membrane Rafts to Caveolae and Subsequent Protein Kinase C-dependent Internalization

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