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The Anchoring Protein RACK1 Links Protein Kinase Cε to Integrin β Chains

REQUIREMENT FOR ADHESION AND MOTILITY*
  • Arnaud Besson
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  • Tammy L. Wilson
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  • V. Wee Yong
    Correspondence
    Canadian Institutes for Health Research scientist and a senior scholar of the Alberta Heritage Foundation for Medical Research. To whom correspondence should be addressed: University of Calgary, 3330 Hospital Dr. N.W., HMRB 191, Calgary, Alberta T2N 4N1, Canada. Tel.: 403-220-8965; Fax: 403-283-8731;
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  • Author Footnotes
    * The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.Thiswork was supported in part by a grant from the Canadian Institutes for Health Research.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
    § Research student of the National Cancer Institute of Canada supported by funds provided by the Terry Fox Run. Present address: Fred Hutchinson Cancer Research Center, Division of Basic Sciences, Seattle, WA 98109.
Open AccessPublished:April 04, 2002DOI:https://doi.org/10.1074/jbc.M111644200
      Integrin affinity is modulated by intracellular signaling cascades, in a process known as “inside-out” signaling, leading to changes in cell adhesion and motility. Protein kinase C (PKC) plays a critical role in integrin-mediated events; however, the mechanism that links PKC to integrins remains unclear. Here, we report that PKCε positively regulates integrin-dependent adhesion, spreading, and motility of human glioma cells. PKCε activation was associated with increased focal adhesion and lamellipodia formation as well as clustering of select integrins, and it is required for phorbol 12-myristate 13-acetate-induced adhesion and motility. We provide novel evidence that the scaffolding protein RACK1 mediates the interaction between integrin β chain and activated PKCε. Both depletion of RACK1 by antisense strategy and overexpression of a truncated form of RACK1 which lacks the integrin binding region resulted in decreased PKCε-induced adhesion and migration, suggesting that RACK1 links PKCε to integrin β chains. Altogether, these results provide a novel mechanistic link between PKC activation and integrin-mediated adhesion and motility.
      ECM
      extracellular matrix
      Ab
      antibody
      ANOVA
      analysis of variance
      BrdUrd
      bromodeoxyuridine
      mAb
      monoclonal antibody
      MTT
      3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
      PBS
      phosphate-buffered saline
      PKC
      protein kinase C
      PMA
      phorbol 12-myristate 13-acetate
      RACK1 receptor for activated C kinase 1
      STAT1, signal transducers and activators of transcription 1
      The tight control of cell adhesion and motility is crucial for a wide variety of physiological and pathological processes such as embryogenesis, inflammation, angiogenesis, wound healing, and tumor metastasis. Integrins are heterodimeric cell surface receptors that mediate cell-cell and cell-extracellular matrix (ECM)1 interactions and have been involved in the regulation of cell growth, migration, survival, and metastasis (
      • Hughes P.E.
      • Pfaff M.
      ,
      • Aplin A.E.
      • Howe A.K.
      • Juliano R.L.
      ,
      • Giancotti F.G.
      • Ruoslahti E.
      ). Eight integrin β subunits and 17 α subunits have been identified to date, and these can form more than 20 distinct heterodimers (
      • Plow E.F.
      • Haast T.A.
      • Zang L.
      • Loftus J.
      • Smith J.W.
      ). Integrin affinity and avidity are modulated by intracellular signaling cascades (“inside-out” signaling), leading to changes in adhesion and motility. Conversely, binding of integrins to ECM proteins elicits signals that are transduced into the cell (“outside-in” signaling) to regulate cell growth, migration, and survival. Integrins are central components of focal adhesions, in which they associate with cytoskeleton-associated proteins such as vinculin, talin, and paxillin, and signaling molecules such as focal adhesion kinase and integrin-linked kinase (
      • Giancotti F.G.
      • Ruoslahti E.
      ,
      • Hemler M.E.
      ). A number of intracellular signaling pathways have been involved in the regulation of integrin adhesive functions, including phosphatidylinositol 3-kinase, and the small GTP-binding proteins of the Ras and Rho families (
      • Hughes P.E.
      • Pfaff M.
      ,
      • Kolanus W.
      • Seed B.
      ). Among the proteins implicated in inside-out signaling, protein kinase C (PKC) has been found in many instances to play a crucial role in modulating integrin-mediated cell adhesion, spreading, and migration. However, the mechanism of action of PKC in these events remains elusive.
      PKC is a family of cofactor-dependent serine/threonine kinases involved in the transduction of various biological signals such as proliferation, differentiation, apoptosis, and migration (
      • Newton A.C.
      ,
      • Mochly-Rosen D.
      • Gordon A.S.
      ,
      • Jaken S.
      • Parker P.J.
      ). Twelve PKC isoforms have been identified so far. They have been divided into three subfamilies based on their cofactor requirements for full activation. Conventional PKCs, α, β1, β2, and γ, require Ca2+, diacylglycerol, and phospholipids such as phosphatidylserine for full activation. Novel PKCs, δ, ε, η, θ, ν, and μ, are Ca2+-independent. Atypical PKCs, ι and ζ, are both Ca2+- and diacylglycerol-independent. Several lines of evidence indicate a critical role for PKC in integrin-mediated events. PKC activity is required for adhesion, spreading, migration, and focal adhesion and actin stress fiber assembly on various ECM substrates (
      • Woods A.
      • Couchman J.R.
      ,
      • Vuori K.
      • Ruoslahti E.
      ,
      • Lewis J.M.
      • Cheresh D.A.
      • Schwartz M.A.
      ,
      • Disatnik M.H.
      • Rando T.A.
      ). In addition to its role in focal adhesion formation, PKC activation induces the translocation of focal adhesion kinase and proline-rich tyrosine kinase 2 to focal adhesions and their tyrosine phosphorylation in various cell systems (
      • Vuori K.
      • Ruoslahti E.
      ,
      • Lewis J.M.
      • Cheresh D.A.
      • Schwartz M.A.
      ,
      • Disatnik M.H.
      • Rando T.A.
      ,
      • DeFilippi P.
      • Venturino M.
      • Gulino D.
      • Duperray A.
      • Boquet P.
      • Fiorentini C.
      • Volpe G.
      • Palmieri M.
      • Silengo L.
      • Tarone G.
      ,
      • Litvak V.
      • Tian D.
      • Shaul Y.D.
      • Lev S.
      ). In some reports, the identity of the PKC isoform involved in integrin-mediated processes has been investigated. It appears that depending on the cell type, different PKC isoforms are involved in the regulation of integrin function (
      • Harrington E.O.
      • Loffler J.
      • Nelson P.R.
      • Kent K.C.
      • Simons M.
      • Ware J.A.
      ,
      • Tang S.
      • Morgan K.G.
      • Parker C.
      • Ware J.A.
      ,
      • Haller H.
      • Lindschau C.
      • Maasch C.
      • Olthoff H.
      • Kurscheid D.
      • Luft F.C.
      ,
      • Laudanna C.
      • Mochly-Rosen D.
      • Liron T.
      • Constantin G.
      • Butcher E.C.
      ,
      • Ng T.
      • Shima D.
      • Squire A.
      • Bastiaens P.I.H.
      • Gschmeissner S.
      • Humphries M.J.
      • Parker P.J.
      ). For example, in breast carcinoma cells, an interaction between integrin β1 and PKCα was demonstrated, and overexpression of PKCα stimulated β1-dependent migration by facilitating integrin β1 endocytosis and recycling to the plasma membrane (
      • Ng T.
      • Shima D.
      • Squire A.
      • Bastiaens P.I.H.
      • Gschmeissner S.
      • Humphries M.J.
      • Parker P.J.
      ). Few studies have focused on the events upstream of PKC in the regulation of integrins (
      • Fahraeus R.
      • Lane D.P.
      ,
      • Klemke R.L.
      • Yebra M.
      • Bayna E.M.
      • Cheresh D.A.
      ,
      • Rabinovitz I.
      • Toker A.
      • Mercurio A.M.
      ). For instance, epidermal growth factor-induced integrin-mediated migration was dependent on PKC activity (
      • Klemke R.L.
      • Yebra M.
      • Bayna E.M.
      • Cheresh D.A.
      ,
      • Rabinovitz I.
      • Toker A.
      • Mercurio A.M.
      ), illustrating the role of PKC in inside-out signaling cascades. However, despite considerable evidence describing the importance of PKC in integrin-mediated events, the mechanism by which PKC regulates these processes remains poorly understood.
      A means of PKC regulation is through their association with targeting proteins, providing a tight control of PKC subcellular localization and substrate specificity (
      • Mochly-Rosen D.
      • Gordon A.S.
      ,
      • Jaken S.
      • Parker P.J.
      ). One such protein, RACK1 (Receptor for ActivatedC-Kinase 1), specifically binds to activated PKC (
      • Mochly-Rosen D.
      • Khaner H.
      • Lopez J.
      ,
      • Ron D.
      • Chen C.H.
      • Caldwell J.
      • Jamieson L.
      • Orr E.
      • Mochly-Rosen D.
      ). RACK1 is a 36-kDa protein formed of seven WD-40 repeats; these repeats are usually involved in protein-protein interactions. RACK1 associates with other signaling proteins such as phospholipase Cγ1 (
      • Disatnik M.H.
      • Hernandez-Sotomayor S.M.T.
      • Jones G.
      • Carpenter G.
      • Mochly-Rosen D.
      ) and the cAMP-specific phosphodiesterase PDE4D5 (
      • Yarwood S.J.
      • Steele M.R.
      • Scotland G.
      • Houslay M.D.
      • Bolger G.B.
      ). RACK1 binding to the type I interferon receptor was required for the recruitment and activation of STAT1 by the receptor (
      • Croze E.
      • Usacheva A.
      • Asarnow D.
      • Minshall R.D.
      • Perez H.D.
      • Colamonici O.
      ,
      • Usacheva A.
      • Smith R.
      • Minshall R.
      • Baida G.
      • Seng S.
      • Croze E.
      • Colamonici O.R.
      ). RACK1 was found to interact with Src family kinases and to inhibit their kinase activity; and RACK1 overexpression inhibited Src activity and cell proliferation (
      • Chang B.Y.
      • Conroy K.B.
      • Machleder E.M.
      • Cartwright C.A.
      ,
      • Chang B.Y.
      • Chiang M.
      • Cartwright C.A.
      ). RACK1 was constitutively bound to the common β chain of the interleukin-5/interleukin-3/granulocyte-macrophage colony-stimulating factor receptors and allowed the recruitment of PKCβ to the receptor after interleukin-5 or PMA stimulation (
      • Geijsen N.
      • Spaargaren M.
      • Raaijmakers J.A.M.
      • Lammers J.W.J.
      • Koenderman L.
      • Coffer P.J.
      ). Thus, RACK1 may act as a scaffold or anchoring protein that regulates the localization of various signaling enzymes to specific subcellular compartments, to allow the formation of signaling complexes. Recently, RACK1 was found to interact with the membrane proximal region of the cytoplasmic tail of integrins β1, β2, β3, and β5, and RACK1-integrin binding was found to be dependent on the presence of PMA, suggesting the involvement of PKC in this interaction (
      • Liliental J.
      • Chang D.D.
      ,
      • Buensuceso C.S.
      • Woodside D.
      • Huff J.L.
      • Plopper G.E.
      • O'Toole T.E.
      ). However, the functional significance of the interaction between RACK1 and integrins and the possible involvement of PKC in this interaction have not been investigated.
      Migration and invasion of glioma cells, leading to tumor recurrence, are a major cause of mortality in glioma patients (
      • Holland E.C.
      ); however, the mechanism that these cells utilize to migrate is poorly understood. We have shown previously that U251N glioma cells express the PKC isoforms α, δ, ε, η, μ, and ζ, and that PKCα controls cell cycle progression and proliferation (
      • Besson A.
      • Yong V.W.
      ). In the present study, we report that PKCε positively regulates integrin-dependent adhesion and motility in glioma cells. PKCε activation induces focal adhesion, lamellipodia formation, and integrin clustering. Moreover, we provide novel evidence of an interaction between PKCε and integrin β chains through the scaffolding protein RACK1 to regulate integrin-mediated adhesion and motility.

      DISCUSSION

      PKC activity plays a critical role in integrin-mediated adhesion, spreading, migration, and focal adhesion assembly (
      • Woods A.
      • Couchman J.R.
      ,
      • Vuori K.
      • Ruoslahti E.
      ,
      • Lewis J.M.
      • Cheresh D.A.
      • Schwartz M.A.
      ,
      • Disatnik M.H.
      • Rando T.A.
      ). However, the mechanism by which PKC regulates integrin functions, and more particularly, how PKC is targeted to the vicinity of integrin, remains unclear. In this report, we found that PKCε is required for integrin-mediated adhesion, migration, and focal adhesion formation in human glioma cells. We found that the mechanism by which PKCε regulates integrin function is through its association with the scaffold protein RACK1 and their association with integrin β chains. Accordingly, the reduction of endogenous RACK1 or PKCε levels, or the overexpression of a dominant negative RACK1 that cannot bind to integrin, attenuated the PMA-induced integrin-mediated adhesion and motility in glioma cells. Overall, these results provide a novel mechanistic link between PKC activation and cell adhesion and motility events. An attractive possibility is that upon activation, PKCε first binds to RACK1 and that in turn this complex associates with integrin β chains, leading to integrin clustering and increased adhesion and motility.
      In human glioma cells, PKCα and ε appear to play opposite roles in the regulation of adhesion, migration, and focal adhesion formation. Similarly, in vascular endothelial cells, different PKC isoforms were found to exert different roles in adhesion or migration. PKCα and θ were found to increase cell migration, without an effect on adhesion, and PKCδ overexpression increased adhesion on vitronectin; furthermore, both PKCα and θ increased cell cycle progression, and PKCδ inhibited proliferation (
      • Harrington E.O.
      • Loffler J.
      • Nelson P.R.
      • Kent K.C.
      • Simons M.
      • Ware J.A.
      ,
      • Tang S.
      • Morgan K.G.
      • Parker C.
      • Ware J.A.
      ). In our system, PKCε acts as a positive regulator of integrin-mediated adhesion and migration of glioma cells, whereas PKCα appears to inhibit these processes. It remains unclear at this point whether the apparent negative role of PKCα in integrin-mediated events involves an active process that leads to focal adhesion disassembly or inhibition of integrin signaling. Another possibility is that PKCα counteracts adhesion and migration by gearing the cell toward a proliferative pathway, likely to be incompatible with motility, as we have shown previously that PKCα is required for cell cycle progression and proliferation in glioma cells (
      • Besson A.
      • Yong V.W.
      ). In contrast, PKCε overexpression or depletion had no effect on cell proliferation. Also, biochemical fractionation of the cells into cytoplasmic and nuclear fractions revealed that both isoforms are targeted to different subcellular localization upon activation with PMA: PKCα is translocated to the nucleus (nuclear envelope), whereas PKCε is retained in the cytoplasmic fraction (plasma membrane), similar to RACK1, providing further evidence for the different roles played by these two isoforms (
      • Besson A.
      • Davy A.
      • Robbins S.M.
      • Yong V.W.
      ). The finding that RACK1 possibly serves as an adaptor between PKCε and select integrin β chains, thus bringing PKC to the close proximity of the focal adhesion machinery, which include several PKC targets, stresses the importance of such anchoring proteins in providing the proper subcellular localization and in regulating the substrate specificity of PKC. We found that the interaction between RACK1 and integrin was dependent on the association of PKCε with RACK1. Liliental and Chang (
      • Liliental J.
      • Chang D.D.
      ) also reported that the association of RACK1 with integrin αLβ2in vivo was dependent on the presence of PMA. Others have shown a coordinated movement of RACK1 with activated PKCβ2 (
      • Ron D.
      • Jiang Z.
      • Yao L.
      • Vagts A.
      • Diamond I.
      • Gordon A.
      ), suggesting that RACK1 acts as a shuttling protein that regulates the movement of active PKC from one subcellular location to another.
      Recently, Berrier et al. (
      • Berrier A.L.
      • Mastrangelo A.M.
      • Downward J.
      • Ginsberg M.
      • LaFlamme S.E.
      ) reported that an activated form of PKCε (Myr-PKCε) could restore the spreading ability of Chinese hamster ovary cells overexpressing a mutant form of β1 integrin in which the cytoplasmic domain of integrin is fused to the extracellular and transmembrane domains of the interleukin-2 receptor. The ability of Myr-PKCε to rescue spreading was dependent upon an intact cytoplasmic domain of the integrin (
      • Berrier A.L.
      • Mastrangelo A.M.
      • Downward J.
      • Ginsberg M.
      • LaFlamme S.E.
      ). Interestingly, the ability of Myr-PKCε to restore β1-mediated spreading required Rac1 activity, indicating that Rac1 is downstream of PKCε in β1 integrin-mediated cell spreading (
      • Berrier A.L.
      • Mastrangelo A.M.
      • Downward J.
      • Ginsberg M.
      • LaFlamme S.E.
      ). Thus PKCε appears to be an important mediator of β integrin functions in various cell systems.
      Buensuceso et al. (
      • Buensuceso C.S.
      • Woodside D.
      • Huff J.L.
      • Plopper G.E.
      • O'Toole T.E.
      ) reported recently that overexpression of RACK1 in Chinese hamster ovary cells resulted in a deficit in cell migration and that mutation of a putative PKC binding site in the third WD-40 repeat prevented this deficit. However, the involvement of PKC was not investigated in that study. These results contrast with ours because we found that RACK1, by mediating the association of PKCε with integrin, plays a positive role in cell migration. One possible explanation is that in their study, overexpression of RACK1 acted in a dominant negative manner because β integrins and PKC were probably in limiting amounts. The excess of RACK1 could have sequestered PKC from a limited number of integrin sites. An alternative hypothesis is that another protein, possibly a PKC isoform, interacts with RACK1 at the third WD-40 repeat to regulate integrin functions negatively.
      What activated PKCε does in glioma cells once it is anchored to integrin β chains by RACK1 remains uncertain. One may expect that activated PKCε phosphorylates a number of targets in focal adhesions, thus facilitating their assembly or increasing their stability and leading to integrin clustering and increased adhesion and migration. PKC has previously been reported to phosphorylate several integrin chains (
      • Rabinovitz I.
      • Toker A.
      • Mercurio A.M.
      ,
      • Gimond C., De
      • Melker A.
      • Aumailley M.
      • Sonnenberg A.
      ), paxillin (
      • DeNichilo M.O.
      • Yamada K.M.
      ), talin (
      • Litchfield D.W.
      • Ball E.H.
      ), and vinculin (
      • Perez-Moreno M.
      • Avila A.
      • Islas S.
      • Sanchez S.
      • Gonzales-Mariscal L.
      ). These phosphorylation events are thought to participate in integrin activation and clustering and focal adhesion assembly and stability. PKCε could also participate in the activation of Rac1, leading to actin rearrangements, lamellipodia formation, and integrin clustering, as suggested by Berrier et al. (
      • Berrier A.L.
      • Mastrangelo A.M.
      • Downward J.
      • Ginsberg M.
      • LaFlamme S.E.
      ).
      In summary, we have found that the scaffolding protein RACK1 targets activated PKCε to integrin β chains, leading to integrin clustering, focal adhesion formation, and increased adhesion and migration. These findings provide a novel mechanism by which PKC regulates integrin function.

      ACKNOWLEDGEMENTS

      We thank Stephen Robbins, Alice Davy, and Michael Walsh for useful discussions and critical reading of this manuscript.

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