Crystallization and preliminary crystallographic studies of CCM3 in complex with the C-terminal domain of MST4

Xu, Xueyong; Wang, Xiaoyan; Ding, Jingjin; Wang, Dacheng

doi:10.1107/s1744309112016843

Cited by 6 publications

(5 citation statements)

References 11 publications

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“…The CCM3/PDCD10 N-terminal α-helical region of approximately 70 residues [24,25] does indeed heterodimerize with the regulatory domains of all three GCKIIIs [23,[26][27][28][29][30]. Furthermore, a recent study showed that essentially full-length CCM3/PDCD10 cocrystallizes with the C-terminus (residues 346-416) of MST4 [31], and even more recently the crystallographic structure of the heterodimer between CCM3/PDCD10 (residues 9-212) and the C-terminus of MST4 (residues 325-413) has been reported [30]. In this complex, MST4 (325-413) assumes a conformation containing three α-helices that interact with the α-helices 1-4 of CCM3/PDCD10 [30].…”

Section: Figure 2 Modelling Of Human Gckiii Structuresmentioning

confidence: 99%

“…The interactions between CCM3/PDCD10 and GCKIIIs [23,26,28,29], and between CCM3/PDCD10 and paxillin [69], suggests that GCKIIIs could be recruited directly to focal adhesions, although (to our knowledge) this has not been demonstrated experimentally. Overexpression of MST3 (431) inhibits cell migration and invasion and is associated with an increase in the phosphorylation at Tyr 31 and Tyr 118 of paxillin [35]. In contrast, depletion of MST3 or overexpression of dominant-negative MST3 (431) (T178A) enhances cell migration and reduces tyrosine residue phosphorylation of paxillin.…”

Section: Gckiiis and Paxillinmentioning

confidence: 99%

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SOcK, MiSTs, MASK and STicKs: the GCKIII (germinal centre kinase III) kinases and their heterologous protein–protein interactions

Sugden

McGuffin

Clerk

2013

Biochemical Journal

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The GCKIII (germinal centre kinase III) subfamily of the mammalian Ste20 (sterile 20)-like group of serine/threonine protein kinases comprises SOK1 (Ste20-like/oxidant-stress-response kinase 1), MST3 (mammalian Ste20-like kinase 3) and MST4. Initially, GCKIIIs were considered in the contexts of the regulation of mitogen-activated protein kinase cascades and apoptosis. More recently, their participation in multiprotein heterocomplexes has become apparent. In the present review, we discuss the structure and phosphorylation of GCKIIIs and then focus on their interactions with other proteins. GCKIIIs possess a highly-conserved, structured catalytic domain at the N-terminus and a less-well conserved C-terminal regulatory domain. GCKIIIs are activated by tonic autophosphorylation of a T-loop threonine residue and their phosphorylation is regulated primarily through protein serine/threonine phosphatases [especially PP2A (protein phosphatase 2A)]. The GCKIII regulatory domains are highly disorganized, but can interact with more structured proteins, particularly the CCM3 (cerebral cavernous malformation 3)/PDCD10 (programmed cell death 10) protein. We explore the role(s) of GCKIIIs (and CCM3/PDCD10) in STRIPAK (striatin-interacting phosphatase and kinase) complexes and their association with the cis-Golgi protein GOLGA2 (golgin A2; GM130). Recently, an interaction of GCKIIIs with MO25 has been identified. This exhibits similarities to the STRADα (STE20-related kinase adaptor α)-MO25 interaction (as in the LKB1-STRADα-MO25 heterotrimer) and, at least for MST3, the interaction may be enhanced by cis-autophosphorylation of its regulatory domain. In these various heterocomplexes, GCKIIIs associate with the Golgi apparatus, the centrosome and the nucleus, as well as with focal adhesions and cell junctions, and are probably involved in cell migration, polarity and proliferation. Finally, we consider the association of GCKIIIs with a number of human diseases, particularly cerebral cavernous malformations.

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Section: Figure 2 Modelling Of Human Gckiii Structuresmentioning

confidence: 99%

Section: Gckiiis and Paxillinmentioning

confidence: 99%

SOcK, MiSTs, MASK and STicKs: the GCKIII (germinal centre kinase III) kinases and their heterologous protein–protein interactions

Sugden

McGuffin

Clerk

2013

Biochemical Journal

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“…The CCM proteins can be found in a dynamic trimeric complex, with CCM2, a scaffolding protein, acting as the hub and interacting directly with CCM1 and CCM3; however, each also interacts with a variety of other signaling, cytoskeletal, and adaptor proteins [60, 87, 88] (Figure 1C). Several additional direct interactors for each of the CCM proteins have been identified, including, for CCM1, the small GTPase RAP1, the membrane anchor protein heart of glass 1 (HEG1) [89], and the integrin cytoplasmic domain associated protein-1 (ICAP1) [90, 91]; for CCM2, MAPK/ERK kinase kinase-3 (MEKK3) (leading to p38 activation) [92, 93]; and for CCM3, the three Germinal Center Kinase III (GCKIII) serine/threonine (STE20) kinases STK24 and STK25 (via which CCM3 interacts with moesin), and MST4, as well as the scaffolding proteins paxillin and striatin (Figure 1C) [94-100]. Of all these bona fide interactors, MEKK3 [92, 93, 101-104], has emerged as a key player in the formation and progression of CCM lesions.…”

Section: Hereditary Hemorrhagic Cerebrovascular Diseasementioning

confidence: 99%

Cerebrovascular disorders associated with genetic lesions

Karschnia

Nishimura

Louvi

2018

Cell. Mol. Life Sci.

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Cerebrovascular disorders are underlain by perturbations in cerebral blood flow and abnormalities in blood vessel structure. Here we provide an overview of current knowledge of select cerebrovascular disorders that are associated with genetic lesions and connect genomic findings with analyses aiming to elucidate the cellular and molecular mechanisms of disease pathogenesis. We argue that a mechanistic understanding of genetic (familial) forms of cerebrovascular disease is a prerequisite for the development of rational therapeutic approaches, and has wider implications for treatment of sporadic (non-familial) forms, which are usually more common.

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“…5O,P). Golgi morphology and deployment, in part regulated by the CCM3 interactor STK25 (Matsuki et al, 2010;Ceccarelli et al, 2011;Xu et al, 2012), were normal (not shown).…”

Section: Ccm3 Affects Neuronal Morphology In Vivo and In Vitromentioning

confidence: 99%

Ccm3, a gene associated with cerebral cavernous malformations, is required for neuronal migration

2014

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Loss of function of cerebral cavernous malformation 3 (CCM3) results in an autosomal dominant cerebrovascular disorder. Here, we uncover a developmental role for CCM3 in regulating neuronal migration in the neocortex. Using cell type-specific gene inactivation in mice, we show that CCM3 has both cell autonomous and cell nonautonomous functions in neural progenitors and is specifically required in radial glia and newly born pyramidal neurons migrating through the subventricular zone, but not in those migrating through the cortical plate. Loss of CCM3 function leads to RhoA activation, alterations in the actin and microtubule cytoskeleton affecting neuronal morphology, and abnormalities in laminar positioning of primarily late-born neurons, indicating CCM3 involvement in radial glia-dependent locomotion and possible interaction with the Cdk5/RhoA pathway. Thus, we identify a novel cytoplasmic regulator of neuronal migration and demonstrate that its inactivation in radial glia progenitors and nascent neurons produces severe malformations of cortical development.

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Crystallization and preliminary crystallographic studies of CCM3 in complex with the C-terminal domain of MST4

Cited by 6 publications

References 11 publications

SOcK, MiSTs, MASK and STicKs: the GCKIII (germinal centre kinase III) kinases and their heterologous protein–protein interactions

SOcK, MiSTs, MASK and STicKs: the GCKIII (germinal centre kinase III) kinases and their heterologous protein–protein interactions

Cerebrovascular disorders associated with genetic lesions

Ccm3, a gene associated with cerebral cavernous malformations, is required for neuronal migration

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