MEGAP impedes cell migration via regulating actin and microtubule dynamics and focal complex formation

Yang, Ying; Marcello, Marco; Endris, Volker; Saffrich, Rainer; Fischer, Roger; Trendelenburg, Michael F.; Sprengel, Rolf; Rappold, Gudrun

doi:10.1016/j.yexcr.2006.04.001

Cited by 54 publications

(55 citation statements)

References 52 publications

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“…In fact, the phenotypes observed in D. discoideum MEGAP mutants (i.e. motility, membrane association) are functionally similar to those reported for mammalian MEGAP (Endris et al, 2002;Soderling et al, 2002;Yang et al, 2006) and FBP17 (Itoh et al, 2005;Tsujita et al, 2006). In addition, our observations of the S. cerevisiae Rgd mutants also point to a role in vacuole regulation.…”

Section: Discussionsupporting

confidence: 85%

“…The srGAP subfamily protein mental retardation GAP (MEGAP) is functionally inactivated in patients with the severe mental retardation disorder 3p -syndrome (Endris et al, 2002). Why the loss of MEGAP causes 3p -syndrome is unknown, but MEGAP is expressed in foetal and adult brain tissue (Endris et al, 2002) and may regulate cell migration (Yang et al, 2006), suggesting that the phenotypes of 3p -syndrome may be due to impaired neuronal migration and axonal connectivity.…”

Section: Introductionmentioning

confidence: 99%

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Dictyostelium MEGAPs: F-BAR domain proteins that regulate motility and membrane tubulation in contractile vacuoles

Heath

Insall

2008

Journal of Cell Science

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PCH family proteins are fundamentally important proteins, linking membrane curvature events with cytoskeletal reorganisation. One group, the MEGAPs (also called srGAPs and WRPs) contain RhoGAP domains in addition to the F-BAR domain. We disrupted MEGAP1 and MEGAP2 in Dictyostelium both singly and in combination. We found a strong cytoskeletal phenotype in MEGAP1– cells and a subtle phototaxis defect in MEGAP2– slugs. MEGAP1–/2– cells have an overabundance of filopodia and slug motility and function are affected. The most dramatic changes, however, are on contractile vacuoles. MEGAP1–/2– cells empty their contractile vacuoles less efficiently than normal and consequently have three times the usual number. GFP-tagged MEGAP1 localises to tubules of the contractile vacuole network and when vacuoles start to empty they recruit cytosolic GFP-MEGAP1. Mutants in the Saccharomyces homologues RGD1 and RGD2 also show abnormal vacuoles, implying that this role is conserved. Thus, MEGAP is an important regulator of the contractile vacuole network, and we propose that tubulation of the contractile vacuole by MEGAP1 represents a novel mechanism for driving vacuole emptying.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Dictyostelium MEGAPs: F-BAR domain proteins that regulate motility and membrane tubulation in contractile vacuoles

Heath

Insall

2008

Journal of Cell Science

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“…Biochemical studies demonstrated that MEGAP possesses GAP activity towards both Rac1 and Cdc42 [21]. Consistent with this, a recent study showed that expression of MEGAP in the neuroblastoma SHSY-5Y cell line leads to a loss of filopodia and lamelliopodia protrusions, which could be rescued by expressing constitutive active forms of Cdc42 or Rac1 [88].…”

Section: Megapmentioning

confidence: 52%

Rho-linked genes and neurological disorders

Kasri

Aelst

2007

Pflugers Arch - Eur J Physiol

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Mental retardation (MR) is a common cause of intellectual disability and affects approximately 2 to 3 % of children and young adults. MR has been consistently associated with changes in dendrites and dendritic spine structure. Given that dendritic spine morphology has been tightly linked to synaptic activity, altered spine morphology has been suggested to be the underlying cause of cognitive disabilities observed in MR. The structure and dynamics of dendritic spines is determined by its underlying actin cytoskeleton. Signaling molecules and cascades important for cytoskeletal regulation have therefore naturally attracted a great deal of attention. As key regulators of both the actin and microtubule cytoskeletons, it is not surprising that the Rho GTPases have emerged as important regulators of dendrite and spine structural plasticity. In support of this, mutations in regulators and effectors of Rho GTPases have been associated with diseases affecting the nervous system, including MR and amyotropic lateral sclerosis (ALS). Here we will discuss Rho GTPase related genes and their signaling pathways involved in MR and ALS.

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“…The SH3 domain of MEGAP is reported to bind to SCAR1/WAVE1 and to have Rac-specific GTPase activity (Soderling et al, 2002). Why the loss of MEGAP causes 3p -syndrome is unknown, but MEGAP is expressed in foetal and adult brain tissue (Endris et al, 2002) and might regulate cell migration (Yang et al, 2006), suggesting that the phenotypes of 3p -syndrome are a result of impaired neuronal migration and axonal connectivity.…”

Section: F-bar Proteins and Diseasementioning

confidence: 99%