Modulation of integrin-linked kinase nucleo-cytoplasmic shuttling by ILKAP and CRM1.
Integrin-linked kinase (ILK) plays key roles in a variety of cell functions, including cell proliferation, adhesion and migration. Within the cell, ILK localizes to multiple sites, including the cytoplasm, focal adhesion complexes that mediate cell adhesion to extracellular substrates, as well as cell-cell junctions in epidermal keratinocytes. Central to understanding ILK function is the elucidation of the mechanisms that regulate its subcellular localization. We now demonstrate that ILK is imported into the nucleus through sequences in its N-terminus, via active transport mechanisms that involve nuclear pore complexes. In addition, nuclear ILK can be rapidly exported into the cytoplasm through a CRM1-dependent pathway, and its export is enhanced by the type 2C protein phosphatase ILKAP. Nuclear localization of ILK in epidermal keratinocytes is associated with increased DNA synthesis, which is sensitive to inhibition by ILKAP. Our studies demonstrate the importance for keratinocyte proliferation of ILK regulation through changes in its subcellular localization, and establish ILKAP and CRM1 as pivotal modulators of ILK subcellular distribution and activity in these cells.
Nakrieko
Kerry-Ann
KA
Department of Physiology and Pharmacology and Regulatory Biology and Functional Genomics Research Group, Siebens-Drake Research Institute, University of Western Ontario, London, Ontario, Canada.
Vespa
Alisa
A
Mason
David
D
Irvine
Timothy S
TS
D'Souza
Sudhir J A
SJ
Dagnino
Lina
L
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002467:Cell Nucleus / Q000201:enzymology*; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004847:Epithelial Cells / Q000201:enzymology; D006367:HeLa Cells; D006801:Humans; D028884:Karyopherins / Q000378:metabolism*; D015603:Keratinocytes / Q000166:cytology / Q000201:enzymology; D051379:Mice; D022022:Nuclear Pore / Q000201:enzymology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D000071636:Protein Phosphatase 2C; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013347:Subcellular Fractions / Q000201:enzymology; D000097606:Exportin 1 Protein; D000099200:Scaffold Protein ILK
D004247:DNA; D028884:Karyopherins; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C; D017346:Protein Serine-Threonine Kinases; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; D000099200:Scaffold Protein ILK