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			PubMed Journals: J Biol Chem

  Source:		PMID: 11788583


    		J Biol Chem. 2002 Mar 29;277(13):10775-82.
     		Epub 2002 Jan 11.

			Keratin 8 phosphorylation by p38 kinase
			regulates cellular keratin filament reorganization:
			modulation by a keratin 1-like disease causing
			mutation.

			Ku NO(1), Azhar S, Omary MB.

			Author Information
			(1) Department of Medicine, and Geriatric
			Research, Education and Clinical Center,
			Veterans Affairs Palo Alto Health Care System,
			Palo Alto, California 94304, USA.

			Keratin 8 (K8) serine 73 occurs within
			a relatively conserved type II keratin motif
			((68)NQSLLSPL) and becomes phosphorylated
			in cultured cells and organs during mitosis,
			cell stress, and apoptosis. Here we show that
			Ser-73 is exclusively phosphorylated in
			vitro by p38 mitogen-activated protein kinase.
			In cells, Ser-73 phosphorylation occurs
			in association with p38 kinase activation
			and is inhibited by SB203580 but not by
			PD98059. Transfection of K8 Ser-73 --> Ala
			or K8 Ser-73 --> Asp with K18 generates
			normal-appearing filaments. In contrast,
			exposure to okadaic acid results in keratin
			filament destabilization in cells expressing
			wild-type or Ser-73 --> Asp K8, whereas
			Ser-73 --> Ala K8-expressing cells maintain
			relatively stable filaments. p38 kinase
			associates with K8/18 immunoprecipitates
			and binds selectively with K8 using an in
			vitro overlay assay. Given that K1 Leu-160
			--> Pro ((157)NQSLLQPL --> (157)NQSPLQPL)
			leads to epidermolytic hyperkeratosis, we
			tested and showed that the analogous K8
			Leu-71 --> Pro leads to K8 hyperphosphorylation
			by p38 kinase in vitro and in transfected
			cells, likely due to Ser-70 neo-phosphorylation,
			in association with significant keratin
			filament collapse upon cell exposure to
			okadaic acid. Hence, K8 Ser-73 is a physiologic
			phosphorylation site for p38 kinase, and
			its phosphorylation plays an important role
			in keratin filament reorganization. The
			Ser-73 --> Ala-associated filament reorganization
			defect is rescued by a Ser-73 --> Asp mutation.
			Also, disease-causing keratin mutations can modulate
			keratin phosphorylation and organization,
			which may affect disease pathogenesis.

			DOI: 10.1074/jbc.M107623200 PMID: 11788583
			[Indexed for MEDLINE]

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