Very-KIND is a novel nervous system specific guanine nucleotide exchange factor for Ras GTPases

Mees, Anaid; Rock, Rebecca E.; Ciccarelli, Francesca D.; Leberfinger, Cornelia B.; Borawski, Johanna M.; Bork, Peer; Wiese, Stefan; Gessler, Manfred; Kerkhoff, Eugen

doi:10.1016/j.modgep.2005.04.015

Cited by 14 publications

(12 citation statements)

References 24 publications

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“…very-KIND (or kinase non-catalytic c-lobe domain (KIND)-containing 1 [Kndc1]) is a RasGEF containing two KIND domains (designated KIND1 and KIND2) (Fig. 7) [27]. We initially isolated very-KIND as a brain-specific gene that is predominantly expressed in granule cells of the IGL after the second postnatal week (Fig.…”

Section: Very-kind (Kndc1): Negative Regulation Of Dendrite Growth Inmentioning

confidence: 99%

Systematizing and Cloning of Genes Involved in the Cerebellar Cortex Circuit Development

et al. 2011

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The cerebellar cortical circuit of mammals develops via a series of magnificent cellular events in the postnatal stage of development to accomplish the formation of functional circuit architectures. The contribution of genetic factors is thought to be crucial to cerebellar development. Therefore, it is essential to analyze the underlying transcriptome during development to understand the genetic blueprint of the cerebellar cortical circuit. In this review, we introduce the profiling of large numbers of spatiotemporal gene expression data obtained by developmental time-series microarray analyses and in situ hybridization cellular mRNA mapping, and the creation of a neuroinformatics database called the Cerebellar Development Transcriptome Database. Using this database, we have identified thousands of genes that are classified into various functional categories and are expressed coincidently with related cellular developmental stages. We have also suggested the molecular mechanisms of cerebellar development by functional characterization of several identified genes (Cupidin, p130Cas, very-KIND, CAPS2) responsible for distinct cellular events of developing cerebellar granule cells. Taken together, the gene expression profiling during the cerebellar development demonstrates that the development of cerebellar cortical circuit is attributed to the complex but orchestrated transcriptome.

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Section: Very-kind (Kndc1): Negative Regulation Of Dendrite Growth Inmentioning

confidence: 99%

Systematizing and Cloning of Genes Involved in the Cerebellar Cortex Circuit Development

et al. 2011

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“…Very-KIND/Kndc1/KIAA1768 (v-KIND) is a Ras guanine nucleotide exchange factor (RasGEF) containing two tandem repeats of the kinase non-catalytic C-lobe domain (KIND), which is thought to be involved in protein-protein interactions [11,12]. In mice, v-KIND is preferentially expressed in various brain regions, with cerebellar granule cells expressing relatively high levels of v-KIND, and expression is sharply increased in post-mitotic cerebellar granule cells between the postnatal first and second weeks, reaching the highest levels in the brain [13].…”

Section: Introductionmentioning

confidence: 99%

The brain-specific RasGEF very-KIND is required for normal dendritic growth in cerebellar granule cells and proper motor coordination

et al. 2017

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Very-KIND/Kndc1/KIAA1768 (v-KIND) is a brain-specific Ras guanine nucleotide exchange factor carrying two sets of the kinase non-catalytic C-lobe domain (KIND), and is predominantly expressed in cerebellar granule cells. Here, we report the impact of v-KIND deficiency on dendritic and synaptic growth in cerebellar granule cells in v-KIND knockout (KO) mice. Furthermore, we evaluate motor function in these animals. The gross anatomy of the cerebellum, including the cerebellar lobules, layered cerebellar cortex and densely-packed granule cell layer, in KO mice appeared normal, and was similar to wild-type (WT) mice. However, KO mice displayed an overgrowth of cerebellar granule cell dendrites, compared with WT mice, resulting in an increased number of dendrites, dendritic branches and terminals. Immunoreactivity for vGluT2 (a marker for excitatory presynapses of mossy fiber terminals) was increased in the cerebellar glomeruli of KO mice, compared with WT mice. The postsynaptic density around the terminals of mossy fibers was also increased in KO mice. Although there were no significant differences in locomotor ability between KO and WT animals in their home cages or in the open field, young adult KO mice had an increased grip strength and a tendency to exhibit better motor performance in balance-related tests compared with WT animals. Taken together, our results suggest that v-KIND is required for compact dendritic growth and proper excitatory synaptic connections in cerebellar granule cells, which are necessary for normal motor coordination and balance.

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“…Instead, it is thought to function as a protein-protein interaction domain (5,19). The KIND domain is detected in proteins of various functions, including the protein tyrosine phosphatase-L1 and the Ras guanine nucleotide exchange factor very-KIND (19,23,24). To date, there are no threedimensional structural data available for any KIND domain.…”

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confidence: 99%

Structure and function of the interacting domains of Spire and Fmn-family formins

Vizcarra

Kreutz

Rodal

et al. 2011

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

158

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Evidence for cooperation between actin nucleators is growing. The WH2-containing nucleator Spire and the formin Cappuccino interact directly, and both are essential for assembly of an actin mesh during Drosophila oogenesis. Their interaction requires the kinase noncatalytic C-lobe domain (KIND) domain of Spire and the C-terminal tail of the formin. Here we describe the crystal structure of the KIND domain of human Spir1 alone and in complex with the tail of Fmn2, a mammalian ortholog of Cappuccino. The KIND domain is structurally similar to the C-lobe of protein kinases. The Fmn2 tail is coordinated in an acidic cleft at the base of the domain that appears to have evolved via deletion of a helix from the canonical kinase fold. Our functional analysis of Cappuccino reveals an unexpected requirement for its tail in actin assembly. In addition, we find that the KIND/tail interaction blocks nucleation by Cappuccino and promotes its displacement from filament barbed ends providing insight into possible modes of cooperation between Spire and Cappuccino.M any processes in the eukaryotic cell depend upon the timely generation and disassembly of actin filaments. The ratelimiting step of filament formation is the creation of a stable actin nucleus. At least three different classes of proteins have evolved to accelerate this step: formins, the Arp2/3 complex, and WiscottAldrich homology 2 (WH2)-domain nucleators (1). How actin nucleators from different classes cooperate to build particular actin structures is an area of intense interest and investigation. For example, the direct biochemical and genetic links between WH2-based Spir (2, 3) and the formin Cappuccino (4) suggest close mechanistic collaboration between these proteins in actin assembly (5-7).Spire (spir) and cappuccino (capu) were first identified in screens for genes affecting embryonic pattern formation in Drosophila melanogaster (Dm) (7). They synergize to build a cytoplasmic actin mesh, and mutation of either of these genes results in loss of this structure, premature microtubule-dependent cytoplasmic streaming, and gross defects in embryonic morphology (8, 9). Mice lacking formin-2 (Fmn2; a mammalian Capu ortholog) exhibit egg failure and female hypofertility (10) due to loss of an actin-based structure during meiosis (11,12), supporting the functional conservation of these proteins in higher eukaryotes.Formins possess an actin-nucleating formin homology 2 (FH2) domain and an adjacent proline-rich FH1 domain (Fig. 1A). The FH2 domain remains bound to the barbed end of the actin filament as additional subunits are added, protecting growing ends from the activity of capping proteins, which would otherwise terminate elongation (13). Fmn-family formins, including Capu and orthologs Fmn1 and Fmn2 (5,14,15), lack obvious regulatory domains found in diaphanous-related formins (DRFs), which include a GTPase-binding domain, diaphanous inhibitory domain, and C-terminal diaphanous autoregulatory domain (DAD) (16,17). Fmn-family formins do have short (approximately 25 ...

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Very-KIND is a novel nervous system specific guanine nucleotide exchange factor for Ras GTPases

Cited by 14 publications

References 24 publications

Systematizing and Cloning of Genes Involved in the Cerebellar Cortex Circuit Development

Systematizing and Cloning of Genes Involved in the Cerebellar Cortex Circuit Development

The brain-specific RasGEF very-KIND is required for normal dendritic growth in cerebellar granule cells and proper motor coordination

Structure and function of the interacting domains of Spire and Fmn-family formins

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