Characterization and chromosomal mapping of a novel human gene, ANKHZN

Kuriyama, Hideyuki; Asakawa, Shuichi; Minoshima, Shinsei; Maruyama, Hiroshi; Ishii, Naoya; Ito, Kenjiro; Gejyo, Fumitake; Arakawa, Masaaki; Shimizu, Nobuyoshi; Kuwano, Ryozo

doi:10.1016/s0378-1119(00)00247-x

Cited by 9 publications

(7 citation statements)

References 34 publications

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“…The corresponding human cDNA was obtained by PCR, using primers derived from the mouse DNA sequence and a random primed HeLa cDNA library as template (Zerial et al 2001). The sequence of the human cDNA matched the recently revised hAnkhzn gene sequence (NP 057460.2) (Kuriyama et al 2000). The predicted human p130 primary sequence consists of an N-terminal BTB/POZ domain, a C-terminal FYVE-finger, and 21 successive ankyrin (ANK) repeats in between these two domains (Figure 1B).…”

Section: Resultsmentioning

confidence: 74%

The Rab5 Effector Rabankyrin-5 Regulates and Coordinates Different Endocytic Mechanisms

et al. 2004

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The small GTPase Rab5 is a key regulator of clathrin-mediated endocytosis. On early endosomes, within a spatially restricted domain enriched in phosphatydilinositol-3-phosphate [PI(3)P], Rab5 coordinates a complex network of effectors that functionally cooperate in membrane tethering, fusion, and organelle motility. Here we discovered a novel PI(3)P-binding Rab5 effector, Rabankyrin-5, which localises to early endosomes and stimulates their fusion activity. In addition to early endosomes, however, Rabankyrin-5 localises to large vacuolar structures that correspond to macropinosomes in epithelial cells and fibroblasts. Overexpression of Rabankyrin-5 increases the number of macropinosomes and stimulates fluid-phase uptake, whereas its downregulation inhibits these processes. In polarised epithelial cells, this function is primarily restricted to the apical membrane. Rabankyrin-5 localises to large pinocytic structures underneath the apical surface of kidney proximal tubule cells, and its overexpression in polarised Madin-Darby canine kidney cells stimulates apical but not basolateral, non-clathrin-mediated pinocytosis. In demonstrating a regulatory role in endosome fusion and (macro)pinocytosis, our studies suggest that Rab5 regulates and coordinates different endocytic mechanisms through its effector Rabankyrin-5. Furthermore, its active role in apical pinocytosis in epithelial cells suggests an important function of Rabankyrin-5 in the physiology of polarised cells.

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Section: Resultsmentioning

confidence: 74%

The Rab5 Effector Rabankyrin-5 Regulates and Coordinates Different Endocytic Mechanisms

et al. 2004

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“…Ankfy1/+ mutant mice show severe ataxia and a substantial loss of Purkinje cells due to increased apoptosis during a period of programmed cell death (PCD). The Ankfy1 protein is ubiquitously expressed in various tissues and in the CNS (Kuriyama et al, 2000). Using in situ hybridization, the Ankfy1 mRNA was specifically expressed in cerebellar Purkinje cells and in the gray matter of the spinal cord.…”

Section: Discussionmentioning

confidence: 99%

“…The human ANKFY1 gene encodes Ankfy1, a multimodular protein consisting of 1166 amino acids that exhibits 84.9% identity to the mouse homolog, which is highly expressed in the adult brain and spinal cord (Kuriyama et al, 2000). From the N- to C-terminus, Ankfy1 contains a BTB/POZ domain that acts as a specific protein-protein interaction interface and mediates protein oligomerization, 21 ankyrin repeats that specifically bind to proteins or macromolecules, and a FYVE-finger domain that encodes a double zinc finger protein in combination with phosphatidylinositol 3-phosphate (PI(3)P), which may be involved in vesicle or protein transport (Kuriyama et al, 2000). The nature of these key features suggests that Ankfy1 may perform special functions.…”

Section: Introductionmentioning

confidence: 99%

Purkinje Cell Degeneration and Motor Coordination Deficits in a New Mouse Model of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

Ding

Weng

Fan

et al. 2017

Front. Mol. Neurosci.

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Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disorder. In 2007, a novel locus, SAX2, which is located on chromosome 17p13 and contains 3 genes, ankyrin repeat and FYVE domain-containing 1 (ANKFY1), β-arrestin 2 (ARRB2) and kinesin family member 1C (KIF1C), was linked to ARSACS. We generated Ankfy1 heterozygous (Ankfy1/+) mice to establish an animal model and examine the pathophysiological basis of ARSACS. The transgenic mice displayed an abnormal gait with progressive motor and cerebellar nerve dysfunction that was highly reminiscent of ARSACS. These clinical features were accompanied by an early-onset and progressive loss of Purkinje cells, followed by gliosis. Additionally, the loss of Ankfy1 function resulted in an abnormal expression of neurotrophic factors (NTFs) in the Ankfy1/+ mouse cerebellum. Moreover, Purkinje cells cultured from neonatal Ankfy1/+ mice exhibited a shorter dendritic length and decreased numbers of dendritic spines. Importantly, cerebellar Purkinje cells from Ankfy1/+ mice and cells transfected with a lentiviral Ankfy1 shRNA underwent apoptosis. We propose that transgenic Ankfy1/+ mice are a useful model for studying the pathogenesis of ARSACS and for exploring the molecular mechanisms involved in this neurodegenerative disease.

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“…Our analysis also identified several previously unidentified potential interactors of Rab7 (Table 2). Of particular note are VapB, the FYVE containing-protein ANKFY1, and SPG21, which localize to membranes and potentially play a role in vesicular transport (38–40). A recent study elegantly demonstrated a role for VapB and VapA in regulating the cholesterol-dependent microtubule trafficking of Rab7-positive late endosomes (41).…”

Section: Discussionmentioning

confidence: 99%

Disease mutations in Rab7 result in unregulated nucleotide exchange and inappropriate activation

McCray

Skordalakes

Taylor

2009

Human Molecular Genetics

102

134

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Rab GTPases are molecular switches that orchestrate vesicular trafficking, maturation and fusion by cycling between an active, GTP-bound form, and an inactive, GDP-bound form. The activity cycle is coupled to GTP hydrolysis and is tightly controlled by regulatory proteins. Missense mutations of the GTPase Rab7 cause a dominantly inherited axonal degeneration known as Charcot-Marie-Tooth type 2B through an unknown mechanism. We present the 2.8 Å crystal structure of GTP-bound L129F mutant Rab7 which reveals normal conformations of the effector binding regions and catalytic site, but an alteration to the nucleotide binding pocket that is predicted to alter GTP binding. Through extensive biochemical analysis, we demonstrate that disease-associated mutations in Rab7 do not lead to an intrinsic GTPase defect, but permit unregulated nucleotide exchange leading to both excessive activation and hydrolysis-independent inactivation. Consistent with augmented activity, mutant Rab7 shows significantly enhanced interaction with a subset of effector proteins. In addition, dynamic imaging demonstrates that mutant Rab7 is abnormally retained on target membranes. However, we show that the increased activation of mutant Rab7 is counterbalanced by unregulated, GTP hydrolysis-independent membrane cycling. Notably, disease mutations are able to rescue the membrane cycling of a GTPase-deficient mutant. Thus, we demonstrate that disease mutations uncouple Rab7 from the spatial and temporal control normally imposed by regulatory proteins and cause disease not by a gain of novel toxic function, but by misregulation of native Rab7 activity.

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Characterization and chromosomal mapping of a novel human gene, ANKHZN

Cited by 9 publications

References 34 publications

The Rab5 Effector Rabankyrin-5 Regulates and Coordinates Different Endocytic Mechanisms

The Rab5 Effector Rabankyrin-5 Regulates and Coordinates Different Endocytic Mechanisms

Purkinje Cell Degeneration and Motor Coordination Deficits in a New Mouse Model of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay

Disease mutations in Rab7 result in unregulated nucleotide exchange and inappropriate activation

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