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BETA
Strömblad, Staffan
Publications (4 of 4) Show all publications
Bao, W. J., Thullberg, M., Zhang, H. Q., Onischenko, A. & Strömblad, S. (2002). Cell attachment to the extracellular matrix induces proteasomal degradation of p21(CIP1) via Cdc42/Rac1 signaling. Molecular and Cellular Biology, 22(13), 4587-4597
Open this publication in new window or tab >>Cell attachment to the extracellular matrix induces proteasomal degradation of p21(CIP1) via Cdc42/Rac1 signaling
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2002 (English)In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 22, no 13, p. 4587-4597Article in journal (Refereed) Published
Abstract [en]

The cyclin-dependent kinase 2 (Cdk2) inhibitors p21(CIP1) and p27(KIP1) are negatively regulated by anchorage during cell proliferation, but it is unclear how integrin signaling may affect these Cdk2 inhibitors. Here, we demonstrate that integrin ligation led to rapid reduction of p21(CIp1) and p27(KIP1) protein levels in three distinct cell types upon attachment to various extracellular matrix (ECM) proteins, including fibronectin (FN), or to immobilized agonistic anti-integrin monoclonal antibodies. Cell attachment to FN did not rapidly influence p21(CIp1) mRNA levels, while the protein stability of p21(CIp1) was decreased. Importantly, the down-regulation of p21(CIP1) and p27(KIP1) was completely blocked by three distinct proteasome inhibitors, demonstrating that integrin ligation induced proteasomal degradation of these Cdk2 inhibitors. Interestingly, ECM-induced proteasomal proteolysis of a ubiquitination-deficient p21(CIP1) mutant (p21K6R) also occurred, showing that the proteasomal degradation of p21(CIP1) was ubiquitin independent. Concomitant with our finding that the small GTPases Cdc42 and Rac1 were activated by attachment to FN, constitutively active (ca) Cdc42 and ca Rac1 promoted down-regulation of p21(CIP1). However, dominant negative (dn) Cdc42 and do Rac1 mutants blocked the anchorage-induced degradation of p21(CIP1), suggesting that an integrin-induced Cdc42/Rac1 signaling pathway activates proteasomal degradation of p21(CIP1). Our results indicate that integrin-regulated proteasomal proteolysis might contribute to anchorage-dependent cell cycle control.

National Category
Biochemistry and Molecular Biology Cell Biology
Identifiers
urn:nbn:se:sh:diva-15795 (URN)10.1128/MCB.22.13.4587-4597.2002 (DOI)000176217100014 ()12052868 (PubMedID)
Available from: 2012-03-07 Created: 2012-03-07 Last updated: 2017-07-20Bibliographically approved
Strömblad, S., Fotedar, A., Brickner, H., Theesfeld, C., de Diaz, E. A., Friedlander, M. & Cheresh, D. A. (2002). Loss of p53 compensates for alpha(v)-integrin function in retinal neovascularization. Journal of Biological Chemistry, 277(16), 13371-13374
Open this publication in new window or tab >>Loss of p53 compensates for alpha(v)-integrin function in retinal neovascularization
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2002 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 277, no 16, p. 13371-13374Article in journal (Refereed) Published
Abstract [en]

alpha(v)-Integrin antagonists block neovascularization in various species, whereas 20% of alpha(v)-integrin null mice are born with many normal looking blood vessels. Given that blockade of alpha(v)-integrins during angiogenesis induces p53 activity, we utilized p53 null mice to elucidate whether loss of p53 can compensate for av-integrin function in neovascularization of the retina. Murine retinal vascularization was inhibited by systemic administration of an alpha(v)-integrin antagonist. In contrast, mice lacking p53 were refractory to this treatment, indicating that neovascularization in normal mice depends on alpha(v)-integrin-mediated suppression of p53. Blockade of alpha(v)-integrins during neovascularization resulted in an induction of p21(CIP1) in wild type and, surprisingly, in p53 null retinas, indicating that alpha(v)-integrin ligation regulates p21(CIP1) levels in a p53-independent manner. In conclusion, we demonstrate for the first time an in vivo intracellular mechanism for compensation of integrin function and that p53 and alpha(v)-integrins act in concert during retinal neovascularization.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:sh:diva-15806 (URN)10.1074/jbc.C200044200 (DOI)000175096000004 ()11856728 (PubMedID)
Available from: 2012-03-08 Created: 2012-03-07 Last updated: 2017-12-07Bibliographically approved
Zhang, H. Q., Li, Z. L., Viklund, E. K. & Strömblad, S. (2002). P21-activated kinase 4 interacts with integrin alpha v beta 5 and regulates alpha v beta 5-mediated cell migration. Journal of Cell Biology, 158(7), 1287-1297
Open this publication in new window or tab >>P21-activated kinase 4 interacts with integrin alpha v beta 5 and regulates alpha v beta 5-mediated cell migration
2002 (English)In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 158, no 7, p. 1287-1297Article in journal (Refereed) Published
Abstract [en]

P21-activated kinase 1 (PAK1) can affect cell migration (Price et al., 1998; del Pozo et al., 2000) and modulate myosin light chain kinase and LIM kinase, which are components of the cellular motility machinery (Edwards, D.C., L.C. Sanders, G.M. Bokoch, and G.N. Gill. 1999. Nature Cell Biol. 1:253-259; Sanders, L.C., F. Matsumura, G.M. Bokoch, and P. de Lanerolle. 1999. Science. 283: 2083-2085). We here present a novel cell motility pathway by demonstrating that PAK4 directly interacts with an integrin intracellular domain and regulates carcinoma cell motility in an integrin-specific manner. Yeast two-hybrid screening identified PAK4 binding to the cytoplasmic domain of the integrin beta5 subunit, an association that was also found in mammalian cells between endogenous PAK4 and integrin alphavbeta5. Furthermore, we mapped the PAK4 binding to the membrane-proximal region of integrin beta5, and identified an integrin-binding domain at aa 505-530 in the COOH terminus of PAK4. Importantly, engagement of integrin alphavbeta5 by cell attachment to vitronectin led to a redistribution of PAK4 from the cytosol to dynamic lamellipodial structures where PAK4 colocalized with integrin alphavbeta5. Functionally, PAK4 induced integrin alphavbeta5-mediated, but not beta1-mediated, human breast carcinoma cell migration, while no changes in integrin cell surface expression levels were observed. In conclusion, our results demonstrate that PAK4 interacts with integrin alphavbeta5 and selectively promotes integrin alphavbeta5-mediated cell migration.

National Category
Cell Biology
Identifiers
urn:nbn:se:sh:diva-15785 (URN)10.1083/jcb.200207008 (DOI)000178407500014 ()12356872 (PubMedID)
Available from: 2012-03-08 Created: 2012-03-07 Last updated: 2017-07-20Bibliographically approved
Bakhiet, M., Tjernlund, A., Mousa, A., Gad, A., Strömblad, S., Kuziel, W. A., . . . Andersson, J. (2001). RANTES promotes growth and survival of human first-trimester forebrain astrocytes. Nature Cell Biology, 3(2), 150-157
Open this publication in new window or tab >>RANTES promotes growth and survival of human first-trimester forebrain astrocytes
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2001 (English)In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 3, no 2, p. 150-157Article in journal (Refereed) Published
Abstract [en]

We have examined the role of alpha and beta chemokines in the promotion of the ontogenetic development of the brain. RANTES was expressed preferentially in human fetal astrocytes in an age-dependent manner. Astrocytes from 5-week-old brains showed high proliferation and reduced survival, whereas 10-week-old astrocytes exhibited opposite effects. These effects were suppressed by anti-RANTES or anti-RANTES receptor antibodies and were enhanced by recombinant RANTES. RANTES induced tyrosine phosphorylation of several cellular proteins and nuclear translocation of STAT-1 in astrocytes. Interferons (IFN-gamma) was required for RANTES effects because RANTES induced IFN-gamma, and only 10-week-old astrocytes expressed the IFN-gamma receptor. Blocking of IFN-gamma with antibody reversed the effects of RANTES, indicating that cytokine/chemokine networks are critically involved in brain development.

National Category
Cell Biology
Identifiers
urn:nbn:se:sh:diva-15871 (URN)10.1038/35055057 (DOI)000166793000016 ()11175747 (PubMedID)2-s2.0-0035154091 (Scopus ID)
Available from: 2012-03-12 Created: 2012-03-09 Last updated: 2017-12-07Bibliographically approved
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