MO25 /  interact with STRAD /  enhancing their ability to bind, activate and localize LKB1 in the cytoplasm

Boudeau, Jérôme; Baas, Annette F.; Deák, Mária; Morrice, Nick; Kieloch, Agnieszka; Schutkowski, Mike; Prescott, Alan R.; Clevers, Hans; Alessi, Dario R.

doi:10.1093/emboj/cdg490

Cited by 398 publications

(423 citation statements)

References 37 publications

(53 reference statements)

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“…LKB1 functions in a heterotrimeric complex with the inactive pseudokinase, STE20-related adaptor, and the armadillo repeat scaffolding-like protein, MO25 Boudeau et al, 2003). The best characterized LKB1 substrate is the AMPK, a sensor of cellular energy status (Hawley et al, 2003).…”

Section: Lkb1 As An Energetic Checkpoint Controllermentioning

confidence: 99%

A role for LKB1 gene in human cancer beyond the Peutz–Jeghers syndrome

2007

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Section: Lkb1 As An Energetic Checkpoint Controllermentioning

confidence: 99%

A role for LKB1 gene in human cancer beyond the Peutz–Jeghers syndrome

2007

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“…MO25 was cloned into BamHI and EcoRI restriction sites of pKH3 (hemagglutinin [HA]-tag) and pKCFP vectors and sequenced. pcDNA3-flagSTRAD␣ and pcDNA3-mycLKB1 were gifts from D. Alessi (Baas et al, , 2004Boudeau et al, 2003Boudeau et al, , 2004. pQE60-CRM1 was a gift from Ian Mattaj (Fornerod et al, 1997;Askjaer et al, 1998Askjaer et al, , 1999.…”

Section: Plasmidsmentioning

confidence: 99%

STRADα Regulates LKB1 Localization by Blocking Access to Importin-α, and by Association with Crm1 and Exportin-7

Dorfman

Macara

2008

MBoC

109

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LKB1, a serine/threonine kinase, regulates cell polarity, metabolism, and cell growth. The activity and cellular distribution of LKB1 are determined by cofactors, STRAD␣ and MO25. STRAD␣ induces relocalization of LKB1 from the nucleus to the cytoplasm and stimulates its catalytic activity. MO25 stabilizes the STRAD␣/LKB1 interaction. We investigated the mechanism of nucleocytoplasmic transport of LKB1 in response to its cofactors. Although LKB1 is imported into the nucleus by importin-␣/␤, STRAD␣ and MO25 passively diffuse between the nucleus and the cytoplasm. STRAD␣ induces nucleocytoplasmic shuttling of LKB1. STRAD␣ facilitates nuclear export of LKB1 by serving as an adaptor between LKB1 and exportins CRM1 and exportin7. STRAD␣ inhibits import of LKB1 by competing with importin-␣ for binding to LKB1. MO25 stabilizes the LKB1-STRAD␣ complex but it does not facilitate its nucleocytoplasmic shuttling. Strikingly, the STRAD␤, isoform which differs from STRAD␣ in the N-and C-terminal domains that are responsible for interaction with export receptors, does not efficiently relocalize LKB1 from the nucleus to the cytoplasm. These results identify a multifactored mechanism to control LKB1 localization, and they suggest that the STRAD␤-LKB1 complex might possess unique functions in the nucleus. INTRODUCTIONPeutz-Jeghers cancer syndrome is caused by mutations in a gene encoding a serine/threonine kinase called LKB1 (Hemminki et al., 1998). This kinase is closely related to PAR-4, a protein required for polarization of the Caenorhabditis elegans zygote, and it has recently been implicated in the apical/basal polarization of mammalian epithelial cells (Baas et al., 2004). LKB1 is also involved in numerous cell signaling pathways that regulate cellular metabolism (Shaw et al., 2004Liang et al., 2007), cell growth, and responses to DNA damage (Wei et al., 2005;Setogawa et al., 2006;Zeng and Berger, 2006). LKB1 can phosphorylate and activate 13 protein kinases from the AMP-activated protein kinase family (Lizcano et al., 2004). However, the biological significance of this phosphorylation is still unclear for many of these kinases. The cellular localization and activity of LKB1 is controlled through its interaction with Ste20 Related Adaptor (STRAD) and an adapter protein, MO25 . STRAD, a 48-kDa protein, is a pseudokinase that consists of a STE20-like kinase domain but lacks several residues that are indespensible for catalytic activity. STRAD resembles most closely the STE20 homologues SPAK (Johnston et al., 2000) and ILPIP (Sanna et al., 2002), or PAP kinase (Nishigaki et al., 2003). Whereas SPAK is a true kinase, it was later shown that ILPIP/PAPK is a pseudokinase, similarly to STRAD and that it also interacts with and activates LKB1. Therefore, it was termed STRAD␤, whereas the original STRAD became known as STRAD␣ . The complex of LKB1 and STRAD␣ or -␤ is stabilized by MO25, a 40-kDa protein composed of ␣-helical repeats that are distantly related to the armadillo repeat domain (Milburn et al., 2004). MO25 binds STRAD ...

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“…Consistent with this possibility, we saw genetic interac- tions between Dmo25 and N and Dl. The mammalian Mo25 protein has been shown to be present in a complex with the Lkb tumor suppressor and the Strad␣ adapter protein (Boudeau et al, 2003). There is no evidence for homologues of Lkb or Strad functioning with Trc or in N signaling.…”

Section: All Ram Pathway Components Do Not Function Along With Trc Inmentioning

confidence: 99%

DrosophilaMob Family Proteins Interact with the Related Tricornered (Trc) and Warts (Wts) Kinases

Emoto

Fang

et al. 2005

MBoC

127

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The function of Tricornered (Trc), the Drosophila Ndr (Nuclear Dbf2-related) serine/threonine protein kinase, is required for the normal morphogenesis of a variety of polarized outgrowths including epidermal hairs, bristles, arista laterals, and dendrites. In yeast the Trc homolog Cbk1 needs to bind Mob2 to activate the RAM pathway. In this report, we provide genetic and biochemical data that Drosophila Trc also interacts with and is activated by Drosophila Dmob proteins. In addition, Drosophila Mob proteins appear to interact with the related Warts/Lats kinase, which functions as a tumor suppressor in flies and mammals. Interestingly, the overgrowth tumor phenotype that results from mutations in Dmob1 (mats) was only seen in genetic mosaics and not when the entire animal was mutant. We conclude that unlike in yeast, in Drosophila individual Mob proteins interact with multiple kinases and that individual NDR family kinases interact with multiple Mob proteins. We further provide evidence that Mo25, the Drosophila homolog of the RAM pathway hym1 gene does not function along with Trc.

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MO25 / interact with STRAD / enhancing their ability to bind, activate and localize LKB1 in the cytoplasm

Cited by 398 publications

References 37 publications

A role for LKB1 gene in human cancer beyond the Peutz–Jeghers syndrome

A role for LKB1 gene in human cancer beyond the Peutz–Jeghers syndrome

STRADα Regulates LKB1 Localization by Blocking Access to Importin-α, and by Association with Crm1 and Exportin-7

DrosophilaMob Family Proteins Interact with the Related Tricornered (Trc) and Warts (Wts) Kinases

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