NDLI: Mammalian Ste20-like Kinase (Mst2) Indirectly Supports Raf-1/ERK Pathway Activity via Maintenance of Protein Phosphatase-2A Catalytic Subunit Levels and Consequent Suppression of Inhibitory Raf-1 Phosphorylation* ♦

Content Provider	PubMed Central
Author	Kilili, Geoffrey K. Kyriakis, John M.
Abstract	Many tumor suppressor proteins act to blunt the effects of mitogenic signaling pathways. Loss of function mutations in the merlin tumor suppressor underlie neurofibromatosis type 2 (NF2), a familial autosomal dominant cancer syndrome. Studies of Drosophila suggest that Hippo (hpo) is required for inhibition of cell proliferation mediated by dMer, the orthologue of human merlin. Mammalian sterile 20-like kinase-2 (Mst2) is a mammalian Hpo orthologue, and numerous studies implicate Mst2 as a tumor suppressor. Mst2 is negatively regulated by the proto-oncoprotein Raf-1 in a manner independent of the kinase activity of Raf-1. We sought to determine whether, in mammalian cells, merlin could positively regulate Mst2. We also sought to determine whether Mst2, in addition to being negatively regulated by Raf-1, might itself reciprocally regulate Raf-1. In contrast to findings from Drosophila, we find no evidence that mammalian merlin positively regulates mammalian Mst2. Instead, surprisingly, RNA interference silencing of Mst2 leads to elevated inhibitory phosphorylation of Raf-1 at Ser-259 and impaired Raf-1 kinase activity. Consequent to this, ERK pathway activation and cell proliferation are attenuated. Phosphatase-2A (PP2A) dephosphorylates Raf-1 Ser-259 in response to mitogens. Interestingly RNA interference silencing of Mst2 triggers a striking proteasome-dependent decrease in the levels of the catalytic subunit of PP2A (PP2A-C). A similar effect is achieved upon silencing of large tumor suppressor (LATS)-1 and LATS2, direct substrates of Mst2. Our studies reveal a more complex role for Mst2 than previously thought. The Mst2 → LATS1/2 pathway, by maintaining PP2A-C levels, may, in some situations, positively affect mitogenic signaling.
Related Links	http://dx.doi.org/10.1074/jbc.m109.078915
Ending Page	15087
Page Count	12
Starting Page	15076
File Format	PDF
ISSN	00219258
e-ISSN	1083351X
Journal	The Journal of Biological Chemistry
Issue Number	20
Volume Number	285
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2010-05-14
Access Restriction	Open
Rights Holder	American Society for Biochemistry and Molecular Biology
Subject Keyword	Cell Biology Biochemistry Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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Mst2 and Mitogens♦ Mammalian Ste20-like Kinase (Mst2) Indirectly Supports Raf-1/ERK Pathway Activity via Maintenance of Protein Phosphatase-2A Catalytic Subunit Levels and Consequent Suppression of Inhibitory Raf-1 Phosphorylation

Mammalian Ste20-like Kinase (Mst2) Indirectly Supports Raf-1/ERK Pathway Activity via Maintenance of Protein Phosphatase-2A Catalytic Subunit Levels and Consequent Suppression of Inhibitory Raf-1 Phosphorylation

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Mammalian Ste20-like Kinase (Mst2) Indirectly Supports Raf-1/ERK Pathway Activity via Maintenance of Protein Phosphatase-2A Catalytic Subunit Levels and Consequent Suppression of Inhibitory Raf-1 Phosphorylation* ♦

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