The endocytic protein GRAF1 is directed to cell-matrix adhesion sites and regulates cell spreading

Doherty, Gary J.; Åhlund, Monika K.; Howes, Mark T.; Morén, Björn; Parton, Robert G.; McMahon, Harvey T.; Lundmark, Richard

doi:10.1091/mbc.e10-12-0936

Cited by 53 publications

(62 citation statements)

References 43 publications

(70 reference statements)

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“…The pathway is highly active and strictly polarizes to the leading edge of migrating cells, in striking contrast to un polarized clathrin-coated pits and caveolae, which are preferentially found at the trailing end of migrating cells 20,23 . CLIC-GEEC carriers fuse with early endosomes in a process that is dependent on phosphatidylinosit o l 3-kinase activity 24 .…”

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confidence: 99%

“…The CLIC-GEEC pathway also has an important role in cell spreading, which is inhibited by the ablation of CLIC-GEEC compartments 20 and by the depletion of GRAF1 (REF. 23). This suggests an interesting 'division of labour' between endocytic pathways.…”

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“…This suggests an interesting 'division of labour' between endocytic pathways. The regulation of active integrins at the surface is maintained by a clathrin-dependent mechanism, whereas membrane remodelling at specific locations might be mediated by the CLIC-GEEC pathway that is located at the leading edge of the cell and enriched at cell-matrix a dhesion sites 23 .…”

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Building endocytic pits without clathrin

Johannes

Parton

Bassereau

et al. 2015

Nat Rev Mol Cell Biol

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How endocytic pits are built in clathrin- and caveolin-independent endocytosis still remains poorly understood. Recent insight suggests that different forms of clathrin-independent endocytosis might involve the actin-driven focusing of membrane constituents, the lectin-glycosphingolipid-dependent construction of endocytic nanoenvironments, and Bin-Amphiphysin-Rvs (BAR) domain proteins serving as scaffolding modules. We discuss the need for different types of internalization processes in the context of diverse cellular functions, the existence of clathrin-independent mechanisms of cargo recruitment and membrane bending from a biological and physical perspective, and finally propose a generic scheme for the formation of clathrin-independent endocytic pits.

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Building endocytic pits without clathrin

Johannes

Parton

Bassereau

et al. 2015

Nat Rev Mol Cell Biol

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216

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“…BAR and PH domains function to regulate endocytosis by binding and inducing membrane curvature (49)(50)(51). A GAP domain inactivates small GTPases by enhancing GTP hydrolysis, and the SH3 domain modulates this GAP activity.…”

Section: Discussionmentioning

confidence: 99%

“…A GAP domain inactivates small GTPases by enhancing GTP hydrolysis, and the SH3 domain modulates this GAP activity. The SH3 domain of Graf1 is reported to bind several other host proteins, including FAK (48,52), PKN␤ (53), and dynamin (50). All of these host factors possess prolinerich motifs that are important for binding with the SH3 domain.…”

Section: Discussionmentioning

confidence: 99%

Graf1 Controls the Growth of Human Parainfluenza Virus Type 2 through Inactivation of RhoA Signaling

Ohta

Goto

Matsumoto

et al. 2016

J Virol

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Rho GTPases are involved in a variety of cellular activities and are regulated by guanine nucleotide exchange factors and GTPase-activating proteins (GAPs). We found that the activation of Rho GTPases by lysophosphatidic acid promotes the growth of human parainfluenza virus type 2 (hPIV-2). Furthermore, hPIV-2 infection causes activation of RhoA, a Rho GTPase. We hypothesized that Graf1 (also known as ARHGAP26), a GAP, regulates hPIV-2 growth by controlling RhoA signaling. Immunofluorescence analysis showed that hPIV-2 infection altered Graf1 localization from a homogenous distribution within the cytoplasm to granules. Graf1 colocalized with hPIV-2 P, NP, and L proteins. Graf1 interacts with P and V proteins via their N-terminal common region, and the C-terminal Src homology 3 domain-containing region of Graf1 is important for these interactions. In HEK293 cells constitutively expressing Graf1, hPIV-2 growth was inhibited, and RhoA activation was not observed during hPIV-2 infection. In contrast, Graf1 knockdown restored hPIV-2 growth and RhoA activation. Overexpression of hPIV-2 P and V proteins enhanced hPIV-2-induced RhoA activation. These results collectively suggested that hPIV-2 P and V proteins enhanced hPIV-2 growth by binding to Graf1 and that Graf1 inhibits hPIV-2 growth through RhoA inactivation. IMPORTANCE Robust growth of hPIV-2 requires Rho activation. hPIV-2 infection causesRhoA activation, which is suppressed by Graf1. Graf1 colocalizes with viral RNP (vRNP) in hPIV-2-infected cells. We found that Graf1 interacts with hPIV-2 P and V proteins. We also identified regions in these proteins which are important for this interaction. hPIV-2 P and V proteins enhanced the hPIV-2 growth via binding to Graf1, while Graf1 inhibited hPIV-2 growth through RhoA inactivation. Rho GTPases are members of the Ras superfamily of 20-to 30-kDa small GTPases. They are highly conserved in eukaryotes and act as molecular switches to regulate essential cellular functions. To date, at least 22 members of the Rho GTPases have been identified in mammalian cells (1, 2). The most well characterized members, namely, RhoA, Cdc42, and Rac1, affect a variety of cellular activities, including actin reorganization, apoptosis, intracellular trafficking, and cell polarity (1-5). Rho GTPases regulate cellular activities by coordinating with other host proteins such as focal adhesion kinase (FAK) and Akt. It is important for viruses to establish an environment that facilitates their growth by controlling these cellular activities. Rho GTPases and their related proteins affect the life cycles of some viruses, including respiratory syncytial virus (RSV) (6, 7), Ebola virus (8), vesicular stomatitis virus (8), Epstein-Barr virus (9), influenza A virus (IAV) (10, 11), and rotavirus (12). The relationship between herpesvirus and Rho GTPases has been well investigated (13). We previously reported that Rho activation promotes syncytium formation induced by human parainfluenza virus type 2 (hPIV-2) (14). However, it remains unknown whe...

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GTPase Regulator Associated with Focal Adhesion Kinase 1 (GRAF1) Immunoglobulin‐Associated Ataxia and Neuropathy

Pittock

Alfugham

O’Connor

et al. 2020

Movement Disord Clin Pract

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Background Background: To date, 10 patients with GTPase Regulator Associated with Focal Adhesion Kinase 1/ Rho GTPase Activating Protein 26-Immunoglobulin (GRAF1/ARHGAP26-IgG) associated neurological disorders have been described, most with ataxia. Objective Objective: To report the clinical, oncological, and radiological associations of GRAF1 autoantibodies. Methods Methods: We identified 17 patients whose serum and/or cerebrospinal fluid IgG was confirmed to target GRAF1/ ARHGAP26-IgG by both tissue-based immunofluorescence and transfected cell-based assay. Clinical information was available on 14 patients. Results Results: The median age at neurological symptom onset was 51 years, and 8 (47%) were men. The predominant clinical features were subacute progressive cerebellar ataxia (13) or peripheral neuropathy (2). Magnetic resonance imaging brain (7 available) showed cerebellar atrophy (4, 1 also cerebrum and brainstem atrophy). Of 7 cerebrospinal fluids available for testing, 5 showed pleocytosis with oligoclonal bands in 3. Squamous cell carcinoma was observed in 3 patients (head and neck [2], lung [1]). Conclusion Conclusion: GTPase Regulator Associated with Focal Adhesion Kinase 1 autoimmunity manifests commonly with subacute ataxia and cerebellar degeneration with a potential association with squamous cell carcinoma. Peripheral neuropathy may also be encountered. Cases in this series responded poorly to immunotherapy. Immunoglobulin-G (IgG) autoantibodies specific for ρ GTPase activating protein 26 (ARHGAP26, also known as GTPase regulator associated with focal adhesion kinase [GRAF1]) have been reported in 10 patients to date. 1-6 Neurological manifestations in decreasing order of frequency included the following: gait ataxia (gait, 7, limb 4), dysarthria (5), nystagmus (5), dizziness (3), cognitive impairment (3), depression (3), hyperkplexia (2), ocular flutter (1), oscillopsia (1), and recurrent psychoses (1). Half of the patients had a tumor, including ovarian cancer (1), breast cancer (1), melanoma (1), B cell lymphoma (1) prostate adenocarcinoma (1), and gastric adenocarcinoma (1), suggesting that this is a paraneoplastic antibody biomarker. 1-6 Here we describe the clinical and oncological associations of an additional 14 GRAF1-IgG-seropositive patients. Methods The Mayo Clinic institutional review board approved this study (08-06647). This is a retrospective, clinical-serological cohort study approved by the institutional review board of Mayo Clinic, with a waiver of consent for clinical data obtained as part of serologic test validation (study 08-00647). All Mayo Clinic patients whose medical records were analyzed provided written consent for medical research.

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The endocytic protein GRAF1 is directed to cell-matrix adhesion sites and regulates cell spreading

Cited by 53 publications

References 43 publications

Building endocytic pits without clathrin

Building endocytic pits without clathrin

Graf1 Controls the Growth of Human Parainfluenza Virus Type 2 through Inactivation of RhoA Signaling

GTPase Regulator Associated with Focal Adhesion Kinase 1 (GRAF1) Immunoglobulin‐Associated Ataxia and Neuropathy

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