MICAL-L1 Links EHD1 to Tubular Recycling Endosomes and Regulates Receptor Recycling

Sharma, Mahak; Giridharan, Sai Srinivas Panapakkam; Rahajeng, Juliati; Naslavsky, Naava; Caplan, Steve

doi:10.1091/mbc.e09-06-0535

Cited by 150 publications

(257 citation statements)

References 38 publications

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“…Gene Knockdown by Silencing RNA (siRNA)-Custom design oligonucleotide duplexes targeting human EHD1 (Naslavsky et al (15)) and ON-TARGETplus SMARTpool siRNA targeting MICAL-L1 and Crmp2 (Dharmacon) were transfected for 72 h using Dharmafect (Dharmacon) as described previously (16).…”

Section: Methodsmentioning

confidence: 99%

“…Immunofluorescence and Uptake Assays-HeLa cells were grown on coverslips, transfected with FuGENE 6 (Roche Applied Science), and fixed with 4% (v/v) paraformaldehyde as described previously (16). In some cases, cytosolic proteins were extracted by treatment for 1 min with 0.05% w/v saponin before fixation.…”

Section: Methodsmentioning

confidence: 99%

“…Moreover, EHD proteins coordinate endocytic transport with Rab proteins through their interactions with common effectors that contain such NPF motifs (9,15). More recently, it was demonstrated that EHD1 interacts with the NPF-containing MICAL family protein, MICAL-L1, a Rab8 effector that localizes to EHD1-containing tubules and regulates endocytic transport and recycling (16).…”

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confidence: 99%

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Collapsin Response Mediator Protein-2 (Crmp2) Regulates Trafficking by Linking Endocytic Regulatory Proteins to Dynein Motors

Rahajeng

Giridharan

Naslavsky

et al. 2010

Journal of Biological Chemistry

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Endocytosis is a conserved cellular process in which nutrients, lipids, and receptors are internalized and transported to early endosomes, where they are sorted and either channeled to degradative pathways or recycled to the plasma membrane. MICAL-L1 and EHD1 are important regulatory proteins that control key endocytic transport steps. However, the precise mechanisms by which they mediate transport, and particularly the mode by which they connect to motor proteins, have remained enigmatic. Here we have identified the collapsin response mediator protein-2 (Crmp2) as an interaction partner of MICAL-L1 in non-neuronal cells. Crmp2 interacts with tubulin dimers and kinesin and negatively regulates dynein-based transport in neuronal cells, but its expression and function in non-neuronal cells have remained poorly characterized. Upon Crmp2 depletion, we observed dramatic relocalization of internalized transferrin (Tf) from peripheral vesicles to the endocytic recycling compartment (ERC), similar to the effect of depleting either MICAL-L1 or EHD1. Moreover, Tf relocalization to the ERC could be inhibited by interfering with microtubule polymerization, consistent with a role for uncoupled motor proteinbased transport upon depletion of Crmp2, MICAL-L1, or EHD1. Finally, transfection of dynamitin, a component of the dynactin complex whose overexpression inhibits dynein activity, prevented the relocalization of internalized Tf to the ERC upon depletion of Crmp2, MICAL-L1, or EHD1. These data provide the first trafficking regulatory role for Crmp2 in non-neuronal cells and support a model in which Crmp2 is an important endocytic regulatory protein that links MICAL-L1⅐EHD1-based vesicular transport to dynein motors.The complexity of the endocytic pathways has broadened in recent years upon discovery of the involvement of the four C-terminal Eps 15 homology domain (EHD) 3 proteins (reviewed in Ref. 1). Since the single Caenorhabditis elegans ortholog (known as RME-1) was originally identified as a regulator of yolk receptor recycling (2), its closest mammalian homolog, EHD1, was found to regulate the recycling of receptors that traverse both the clathrin-dependent (3, 4) and the clathrin-independent (5, 6) internalization pathways. Despite similarities to the Ras family of GTP-binding proteins (5, 7), EHD proteins bind and hydrolyze ATP (7-9), a function necessary for their localization to tubular and vesicular membranes (5,7,10).Proteins that contain EH domains interact with the tripeptide asparagine-proline-phenylalanine (NPF) (11). Recent studies have determined that the EH domains of the C-terminal EHD proteins have a highly positively charged surface (12) and selectively interact with NPF motifs followed by clusters of acidic residues (13, 14). Moreover, EHD proteins coordinate endocytic transport with Rab proteins through their interactions with common effectors that contain such NPF motifs (9, 15). More recently, it was demonstrated that EHD1 interacts with the NPF-containing MICAL family protein, MICAL-L1, a Rab8 ef...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Collapsin Response Mediator Protein-2 (Crmp2) Regulates Trafficking by Linking Endocytic Regulatory Proteins to Dynein Motors

Rahajeng

Giridharan

Naslavsky

et al. 2010

Journal of Biological Chemistry

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“…29 Follow-up studies further suggested that Arf6 can recruit MICAL-L1 onto tubular endosomes, 30 suggesting that Arf6 can regulate Rab8 In mammalian systems, Rab35(GTP) recruits ACAP2/Arf GAP and thus regulates Arf6 activity. Rab35-mediated regulation of Arf6 via ACAP2 is important for NGF-induced outgrowth of neurite and phagocytosis.…”

Section: 28mentioning

confidence: 99%

Interactions between Rab and Arf GTPases regulate endosomal phosphatidylinositol-4,5-bisphosphate during endocytic recycling

Shi

Grant

2013

Small GTPases

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A fter endocytosis, a selective endocytic recycling process returns many endocytosed molecules back to the plasma membrane. The RAB-10/Rab10 GTPase is known to be a key recycling regulator for specific cargo molecules. New evidence, focused on C. elegans RAB-10 in polarized epithelia, points to a key role of RAB-10 in the regulation of endosomal phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) levels. In turn, PI(4,5)P2 levels strongly influence the recruitment of many peripheral membrane proteins, including those important for vesicle budding through their membrane bending activities. Part of the effect of RAB-10 on endosomal PI(4,5)P2 is through its newly identified effector CNT-1, a predicted GTPase activating protein (GAP) of the small GTPase ARF-6/ Arf6. In mammals PI(4,5)P2 generating enzymes are known Arf6 effectors. In C. elegans we found that RAB-10, CNT-1 and ARF-6 are present on the same endosomes, that RAB-10 recruits CNT-1 to endosomes, and that loss of CNT-1 or RAB-10 leads to overaccumulation of endosomal PI(4,5)P2, presumably via hyperactivation of endosomal ARF-6. In turn this leads to over-recruitment of PI(4,5)P2-dependent membrane-bending proteins RME-1/Ehd and SDPN-1/ Syndapin/PACSIN. Conversely, in arf-6 mutants, endosomal PI(4,5)P2 levels were reduced and endosomal recruitment of RME-1 and SDPN-1 failed. This work makes an unexpected link between distinct classes of small GTPases that control endocytic recycling, and provides insight into how this interaction affects

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“…8D, I). Integrins are known to be recycled through Rab11-, Rab8-and Rab4-dependent pathways (Bridgewater et al, 2012;Margadant et al, 2011;Sharma et al, 2009). To find an explanation why FA turnover and recycling of integrins in shR1 cells are increased (as shown in Fig.…”

Section: Reggie-1 Controls the Number Of Fas Via Rab11amentioning

confidence: 99%

Reggie-1/Flotillin-2 regulates integrin trafficking and focal adhesion turnover via Rab11a

Hülsbusch

Solis

Katanaev

et al. 2015

European Journal of Cell Biology

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a b s t r a c tReggies/flotillins are implicated in trafficking of membrane proteins to their target sites and in the regulation of the Rab11a-dependent targeted recycling of E-cadherin to adherens junctions (AJs). Here we demonstrate a function of reggies in focal adhesion (FA) formation and ␣5-and ␤1-integrin recycling to FAs. Downregulation of reggie-1 in HeLa and A431 cells by siRNA and shRNA increased the number of FAs, impaired their distribution and modified FA turnover. This was coupled to enhanced focal adhesion kinase (FAK) and Rac1 signaling and gain in plasma membrane motility. Wild type and constitutively-active (CA) Rab11a rescued the phenotype (normal number of FAs) whereas dominant-negative (DN) Rab11a mimicked the loss-of-reggie phenotype in control cells. That reggie-1 affects integrin trafficking emerged from the faster loss of internalized antibody-labeled ␤1-integrin in reggie-deficient cells. Moreover, live imaging using TIRF microscopy revealed vesicles containing reggie-1 and ␣5-or ␤1-integrin, trafficking close to the substrate-near membrane and making kiss-and-run contacts with FAs. Thus, reggie-1 in interaction with Rab11a controls Rac1 and FAK activation and coordinates the targeted recycling of ␣5-and ␤1-integrins to FAs to regulate FA formation and membrane dynamics.

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MICAL-L1 Links EHD1 to Tubular Recycling Endosomes and Regulates Receptor Recycling

Cited by 150 publications

References 38 publications

Collapsin Response Mediator Protein-2 (Crmp2) Regulates Trafficking by Linking Endocytic Regulatory Proteins to Dynein Motors

Collapsin Response Mediator Protein-2 (Crmp2) Regulates Trafficking by Linking Endocytic Regulatory Proteins to Dynein Motors

Interactions between Rab and Arf GTPases regulate endosomal phosphatidylinositol-4,5-bisphosphate during endocytic recycling

Reggie-1/Flotillin-2 regulates integrin trafficking and focal adhesion turnover via Rab11a

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