Modulation of integrin signal transduction by ILKAP, a protein phosphatase 2C associating with the integrin-linked kinase, ILK1

被引:118
作者
Leung-Hagesteijn, C
Mahendra, A
Naruszewicz, I
Hannigan, GE [1 ]
机构
[1] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada
[2] Hosp Sick Children, Res Inst, Cell Biol Program, Toronto, ON M5G 1X8, Canada
关键词
beta-catenin; GSK3; beta; integrin-linked kinase; protein phosphatase 2C; signal transduction;
D O I
10.1093/emboj/20.9.2160
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
ILKAP, a protein serine/threonine (S/T) phosphatase of the PP2C family, was isolated in a yeast two-hybrid screen baited with integrin-linked kinase, ILK1, Association of ILK1 and ILKAP was independent of the catalytic activity of either partner, as assayed in co-precipitation and two-hybrid experiments. Conditional expression of ILKAP in HEK 293 cells resulted in selective inhibition of ECM- and growth factor-stimulated ILK1 activity, but did not inhibit Raf-l kinase activity. A catalytic mutant of ILKAP, H154D, did not inhibit ILK1 kinase activity. Two cellular targets of ILK1, glycogen synthase kinase 3 beta (GSK3 beta) and protein kinase B (PKB)/AKT, were differentially affected by ILKAP-mediated inhibition of ILK1, Catalytically active, but not mutant ILKAP, strongly inhibited insulin-like growth factor-1-stimulated GSK3 beta phosphorylation on Ser9, but did not affect phosphorylation of PKB on Ser473, suggesting that ILKAP selectively affects ILK-mediated GSK3 beta signalling. Consistent with this, active, but not H154D mutant or the related PP2C alpha, selectively inhibited transactivation of a Tcf/Lef reporter gene, TOPFlash, in 293 cells. We propose that ILKAP regulates ILK1 activity, targeting ILK1 signalling of Wnt pathway components via modulation of GSK3 beta phosphorylation.
引用
收藏
页码:2160 / 2170
页数:11
相关论文
共 33 条
  • [1] beta-catenin is a target for the ubiquitin-proteasome pathway
    Aberle, H
    Bauer, A
    Stappert, J
    Kispert, A
    Kemler, R
    [J]. EMBO JOURNAL, 1997, 16 (13) : 3797 - 3804
  • [2] A novel integrin-activated pathway forms PKB/Akt-stimulatory phosphatidylinositol 3,4-bisphosphate via phosphatidylinositol 3-phosphate in platelets
    Banfic, H
    Tang, XW
    Batty, IH
    Downes, CP
    Chen, CS
    Rittenhouse, SE
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (01) : 13 - 16
  • [3] The structure and mechanism of protein phosphatases: Insights into catalysis and regulation
    Barford, D
    Das, AK
    Egloff, MP
    [J]. ANNUAL REVIEW OF BIOPHYSICS AND BIOMOLECULAR STRUCTURE, 1998, 27 : 133 - 164
  • [4] Barker N, 2000, ADV CANCER RES, V77, P1
  • [5] The integrin-linked kinase regulates the cyclin D1 gene through glycogen synthase kinase 3β and cAMP-responsive element-binding protein-dependent pathways
    D'Amico, M
    Hulit, J
    Amanatullah, DF
    Zafonte, BT
    Albanese, C
    Bouzahzah, B
    Fu, MF
    Augenlicht, LH
    Donehower, LA
    Takemaru, KI
    Moon, RT
    Davis, R
    Lisanti, MP
    Shtutman, M
    Zhurinsky, J
    Ben-Ze'ev, A
    Troussard, AA
    Dedhar, S
    Pestell, RG
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (42) : 32649 - 32657
  • [6] PTEN is inversely correlated with the cell survival factor Akt/PKB and is inactivated via multiple mechanisms in haematological malignancies
    Dahia, PLM
    Aguiar, RCT
    Alberta, J
    Kum, JB
    Caron, S
    Sill, H
    Marsh, DJ
    Ritz, J
    Freedman, A
    Stiles, C
    Eng, C
    [J]. HUMAN MOLECULAR GENETICS, 1999, 8 (02) : 185 - 193
  • [7] Crystal structure of the protein serine/threonine phosphatase 2C at 2.0 angstrom resolution
    Das, AK
    Helps, NR
    Cohen, PTW
    Barford, D
    [J]. EMBO JOURNAL, 1996, 15 (24) : 6798 - 6809
  • [8] Dedhar S, 1999, Curr Opin Hematol, V6, P37, DOI 10.1097/00062752-199901000-00007
  • [9] Integrin cytoplasmic interactions and bidirectional transmembrane signalling
    Dedhar, S
    Hannigan, GE
    [J]. CURRENT OPINION IN CELL BIOLOGY, 1996, 8 (05) : 657 - 669
  • [10] Integrin-linked kinase (ILK): a regulator of integrin and growth-factor signalling
    Dedhar, S
    Williams, B
    Hannigan, G
    [J]. TRENDS IN CELL BIOLOGY, 1999, 9 (08) : 319 - 323