Identification of a Human Brain-specific Isoform of Mammalian STE20-like Kinase 3 That Is Regulated by cAMP-dependent Protein Kinase

Zhou, Tian; Ling, Kun; Guo, Jun; Zhou, Hui Ren; Wu, Ya Lan; Jing, Qing; Ma, Lan; Pei, Gang

doi:10.1074/jbc.275.4.2513

Cited by 38 publications

(47 citation statements)

References 49 publications

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“…The anti-Mst3b antibody labeled neurons specifically ( Fig. 1 D and E), consistent with earlier reports on the distribution of the mRNA (18). Preincubating the antibody with the Mst3b Nterminal peptide blocked immunostaining (data not shown).…”

Section: Resultssupporting

confidence: 79%

“…1 A). One of these variants, Mst3b, has been shown to be neuron-specific in its expression (18), although no specific functions have been ascribed to it as yet. For clarity, we shall refer to the variant discovered first as Mst3a.…”

Section: Resultsmentioning

confidence: 99%

“…Mst3b is a neuron-specific homolog of Ste20, a serinethreonine kinase that controls bud formation in yeast via a MAP kinase signaling pathway (16,18). Other Ste20-like kinases control other modular MAP kinase signaling pathways that regulate diverse aspects of cellular differentiation (17).…”

Section: Discussionmentioning

confidence: 99%

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Mst3b, a purine-sensitive Ste20-like protein kinase, regulates axon outgrowth

Irwin

Li²,

O'Toole³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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The growth of axons is fundamental to the development and repair of brain circuitry. We show here that Mst3b, a neuron-specific homolog of the yeast kinase Ste20, is critical for axon outgrowth. Mst3b is activated in response to trophic factors, and suppressing its expression (via siRNAs) or its function (by a dominant-negative mutant) blocks axon outgrowth. Inosine, a purine nucleoside that stimulates axon outgrowth, activates Mst3b kinase activity, whereas 6-thioguanine, a purine analog that blocks outgrowth, inhibits the activity of this kinase. These findings place Mst3b as a key regulator of axon outgrowth and help explain the purine sensitivity of this process.A xon outgrowth begins shortly after neurons undergo final cell division, and it ends when axon terminals reach their appropriate targets. Although this process is not normally reactivated in the mature CNS after injury, some degree of CNS regeneration has been achieved experimentally by altering neurons' intrinsic growth state and by counteracting inhibitory signals associated with myelin, the perineuronal net, or a glial scar (1-5). Thus, understanding the mechanisms that underlie axon growth not only affords insight into how the brain's circuitry develops but may also enable us to improve functional outcome after stroke, trauma, or neurodegenerative disorders.The purine nucleoside inosine stimulates axon outgrowth in certain types of neurons in culture and in vivo after CNS injury (6-10). The purine analog 6-thioguanine (6-TG), on the other hand, blocks outgrowth induced by neurotrophic factors (9,11,12), and this effect is paralleled by the inhibition of a previously unidentified 45-50 kDa serine-threonine protein kinase (13). Inosine competitively reverses the inhibitory effects of 6-TG on outgrowth (7, 9), suggesting that it may act as an agonist of the 6-TG-sensitive kinase. We now identify the purine-sensitive kinase as mammalian Ste20-like protein kinase-3b (Mst3b) and show that it is a key regulator of axon outgrowth.

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Section: Resultssupporting

confidence: 79%

Section: Resultsmentioning

confidence: 99%

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Mst3b, a purine-sensitive Ste20-like protein kinase, regulates axon outgrowth

Irwin

Li²,

O'Toole³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…While the biological functions of MST3 remains to be de®ned, MST3 was shown to activate ERK in HEK293 cells, consistent with the data reported here for MST4 (Zhou et al, 2000). It should be noted that while the kinase domain between MST3 and 4 share a high degree of homology, the carboxyl terminal domains for these two kinases are entirely di erent.…”

Section: Discussionsupporting

confidence: 78%

“…Not all GCK family members are involved in modulating the activity of JNK/SAPK. MST3 and STE20/SPS1-related proline alanine-rich kinase (SPAK), for instance, respectively activate p42/44 ERK and p38 MAPK, but not JNK (Johnston et al, 2000;Zhou et al, 2000). There are also GCK members including Ste20/oxidant stress response kinase-1 (SOK-1) (Pombo et al, 1996(Pombo et al, , 1997, lymphocyte-oriented kinase (LOK) (Endo et al, 2000;Kuramochi et al, 1997), and Proline-and alanine-rich Ste20-related kinase (PASK) (Tsutsumi et al, 2000), which do not activate any of the known MAPK pathways.…”

Section: Introductionmentioning

confidence: 99%

MST4, a new Ste20-related kinase that mediates cell growth and transformation via modulating ERK pathway

et al. 2001

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In this study, we report the cloning and characterization of a novel human Ste20-related kinase that we designated MST4 (accession number AF231012). The 416 amino acid full-length MST4 contains an aminoterminal kinase domain, which is highly homologous to MST3 and SOK, and a unique carboxy-terminal domain. Northern blot analysis indicated that MST4 is highly expressed in placenta, thymus, and peripheral blood leukocytes. Wild-type but not kinase-dead MST4 can phosphorylate myelin basic protein in an in vitro kinase assay. MST4 speci®cally activates ERK but not JNK or p38 MAPK in transient transfected cells or in stable cell lines. Overexpression of dominant negative MEK1 or treatment with PD98059 abolishes MST4-induced ERK activity, whereas dominant-negative Ras or c-Raf-1 mutants failed to do so, indicating MST4 activates MEK1/ERK via a Ras/Raf-1 independent pathway. HeLa and Phoenix cell lines overexpressing wild-type, but not kinase-dead, MST4 exhibit increased growth rate and form aggressive soft-agar colonies. These phenotypes can be inhibited by PD98059. These results provide the ®rst evidence that MST4 is biologically active in the activation of MEK/ERK pathway and in mediating cell growth and transformation. Oncogene (2001) 20, 6559 ± 6569.

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