Protein kinase Cα activates RAF-1 by direct phosphorylation

Kölch, Walter; Heidecker, Gisela; Kochs, Georg; Hummel, Richard; Vahidi, H; Mischak, Harald; Finkenzeller, Günter; Marmé, Dieter; Rapp, Ulf R.

doi:10.1038/364249a0

Cited by 1,238 publications

(799 citation statements)

References 12 publications

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“…One possible mechanism for integration of the PKC signal into the MAPK cascade, which is consistent with its activation by G protein-coupled receptors [76], is that PKC is required to activate Raf-1. In addition to tyrosine kinase-dependent phosphorylation of Raf-1 by polypeptide growth factors, direct phosphorylation by PKCa is reported to stimulate the catalytic activity of Raf-1 [96]. In support of this, direct activators of PKC (phorbol esters) [82], as well as agonists which utilize the PKC pathway such as ET-1 [76] and 5-HT [50], activate Raf-1 kinase activity in airway smooth muscle cells.…”

Section: Interaction Of Protein Kinase C With Other Signalling Molecumentioning

confidence: 92%

Phenotypic diversity and molecular mechanisms of airway smooth muscle proliferation in asthma

Hirst¹,

Walker²,

Chilvers³

2000

Eur Respir J

109

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Chronic persistent asthma is characterized by poorly reversible airflow obstruction and airways inflammation and remodelling. Histopathological studies of airways removed at post mortem from patients with severe asthma reveal marked inflammatory and architectural changes associated with airway wall thickening. Increased airway smooth muscle content, occurring as a result of hyperplastic and/or hypertrophic growth, is believed to be one of the principal contributors to airway wall thickening. In recent years, significant advances have been made in elucidating the mediators and the intracellular pathways that regulate proliferation of airway smooth muscle. The contribution that smooth muscle makes to persistent airflow obstruction may not, however, be limited simply to its increased bulk within the airway wall. Interest is growing in the possibility that reversible phenotypic modulation and increased heterogeneity of airway smooth muscle function may also be a feature of the asthmatic airway. This review focuses on possible mechanisms controlling smooth muscle phenotype heterogeneity as well as on the mediators and intracellular pathways implicated in its cellular proliferation. Particular attention is paid to mechanisms involving activation of the extracellular signal regulated kinase‐, protein kinase C‐ and phosphoinositide 3‐kinase‐dependent pathways, since these appear to be the major candidate second messenger pathways for G protein‐ and tyrosine kinase‐coupled receptor‐stimulated proliferation.

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Section: Interaction Of Protein Kinase C With Other Signalling Molecumentioning

confidence: 92%

Phenotypic diversity and molecular mechanisms of airway smooth muscle proliferation in asthma

Hirst¹,

Walker²,

Chilvers³

2000

Eur Respir J

109

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“…Once again, Raf-1 was found associated with c-N-ras in both cell lines. The possibility that other Raf family kinases (B-Raf and ARaf) might associate with Ras in vivo was tested using the pan-reactive Raf monoclonal antibody, PBB-1 (Kolch et al, 1990). Figure 6g indicated that, in V12H10 and K61N10 cells, only one Raf family kinase co-immunoprecipitated with N-ras, and this Raf protein co-migrated with Raf-1.…”

Section: Raf-1 Co-immunoprecipitates With N-ras But Not Ha-rasmentioning

confidence: 99%

Ha-ras and N-ras regulate MAPK activity by distinct mechanisms in vivo

Hamilton

Wolfman

1998

Oncogene

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The Ras GTPases function as molecular switches, regulating a multiplicity of biological events. However the contribution, if any, of a speci®c c-Ras isoform (Ha-, N-, or Ki-ras A or B) in the regulation of a given biological or biochemical process, is unknown. Murine C3H10T1/2 ®broblasts transformed with activated (G12V)Ha-ras or (Q61K)N-ras proliferate in serum-free media and have constitutive MAPK activity. The growth factor antagonist, suramin, inhibited the serum-independent proliferation of Ha-ras transformed ®broblasts, but not the serum-independent proliferation of N-ras transformed cells. The inhibition of cell proliferation was concomitant with the abrogation of the constitutive MAPK activity in the Ha-ras transformed ®broblasts. Analysis of the Ras-signalling complexes in immunoprecipitates from Ha-ras transformed cells revealed that Raf-1 co-immunoprecipitated with endogenous c-N-ras but not (G12V)Ha-ras. Pretreatment with suramin resulted in the loss of Raf-1 from c-N-ras immunoprecipitates. A c-N-ras antisense oligonucleotide, which down-regulated c-N-ras protein levels, abrogated the constitutive MAPK activity and serum-independent proliferation of (G12V)Ha-ras transformed cells. The data suggest that Raf-1 has a higher a nity for N-ras then Ha-ras in vivo, and c-N-ras function is required for the serum-independent proliferation of Ha-ras transformed cells.

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“…At the membrane Raf-1 is activated partially by interactions with Ras (Drugan et al, 1996;Mineo et al, 1997;Roy et al, 1997;Stokoe and McCormick, 1997) but also by other mechanisms that require phosphorylation of tyrosine (Fabian et al, 1993;Dent et al, 1995a;Marais et al, 1995;Jelinek et al, 1996) and the presence of certain serine and threonine residues which may be phosphorylated (Fabian et al, 1993;Dent et al, 1995a;Diaz et al, 1997). Candidate kinases that may regulate Raf-1 activity at the plasma membrane include the sca old protein KSR (Yao et al, 1995;Therrien et al, 1996;Zhang et al, 1997), protein kinase C (Kolch et al, 1993), cAMP-dependent protein kinase or protein kinase A (Kikuchi and Williams, 1996) and AMP-activated protein kinase (Sprenkle et al, 1997). Activated Raf-1 phosphorylates and activates MEK1 and MEK2 which in turn phosphorylate and activate ERK1 and ERK2 (Marais and Marshall, 1996;Pritchard and McMahon, 1997).…”

Section: Introductionmentioning

confidence: 99%