Role of the EHD Family of Endocytic Recycling Regulators for TCR Recycling and T Cell Function

Iseka, Fany; Goetz, Benjamin T.; Mushtaq, Insha; An, Wei; Cypher, Luke R; Bielecki, Timothy A.; Tom, Eric; Arya, Priyanka; Bhattacharyya, Sohinee; Storck, Matthew D.; Semerad, Craig L.; Talmadge, James E.; Mosley, R. Lee; Band, Vimla

doi:10.4049/jimmunol.1601793

Cited by 14 publications

(11 citation statements)

References 79 publications

(85 reference statements)

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“…Our inability to show an impact of EHD1 depletion on surface MHC-I levels is likely to reflect our methodology (designed to detect the trafficking of newly synthesized RTKs) since endocytic recycling of MHC-I, tracked using antibody binding at the cell surface, is known to be impaired upon EHD1 KD (23). While our studies have focused on EHD1, it will be important in future studies to assess any roles of the other EHD family members in the Golgi compartment-to-surface exit of EGFR and other RTKs, given their redundant roles that we have observed in other biological systems (34,76,77).…”

Section: Discussionmentioning

confidence: 96%

EHD1 and RUSC2 Control Basal Epidermal Growth Factor Receptor Cell Surface Expression and Recycling

Tom

Mushtaq

Mohapatra

et al. 2020

Molecular and Cellular Biology

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Epidermal growth factor receptor (EGFR) is a prototype receptor tyrosine kinase and an oncoprotein in many solid tumors. Cell surface display of EGFR is essential for cellular responses to its ligands. While postactivation endocytic trafficking of EGFR has been well elucidated, little is known about mechanisms of basal/preactivation surface display of EGFR. Here, we identify a novel role of the endocytic regulator EHD1 and a potential EHD1 partner, RUSC2, in cell surface display of EGFR. EHD1 and RUSC2 colocalize with EGFR in vesicular/tubular structures and at the Golgi compartment. Inducible EHD1 knockdown reduced the cell surface EGFR expression with accumulation at the Golgi compartment, a phenotype rescued by exogenous EHD1. RUSC2 knockdown phenocopied the EHD1 depletion effects. EHD1 or RUSC2 depletion impaired the EGF-induced cell proliferation, demonstrating that the novel, EHD1- and RUSC2-dependent transport of unstimulated EGFR from the Golgi compartment to the cell surface that we describe is functionally important, with implications for physiologic and oncogenic roles of EGFR and targeted cancer therapies.

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Section: Discussionmentioning

confidence: 96%

EHD1 and RUSC2 Control Basal Epidermal Growth Factor Receptor Cell Surface Expression and Recycling

Tom

Mushtaq

Mohapatra

et al. 2020

Molecular and Cellular Biology

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“…A previously uncharacterized role has been recently ascribed to Eps15 homology domain (EHD) family proteins in constitutive TCR recycling to ensure optimal levels of surface TCR levels for subsequent T cell activation (Iseka et al, 2018). These proteins, that include EHD1-4, interact with Rab5, Rab11, Rab8a, and the respective effectors Rabenosyn-5, Rab11-FIP2 and MICAL-L1, regulating cargo recycling through the ERC (Naslavsky et al, 2006; Rahajeng et al, 2009; Sharma et al, 2009).…”

Section: An Endocytic View Of the Immune Synapsementioning

confidence: 99%

Orchestration of Immunological Synapse Assembly by Vesicular Trafficking

Onnis

Baldari

2019

Front. Cell Dev. Biol.

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Ligation of the T-cell antigen receptor (TCR) by cognate peptide bound to the Major Histocompatibility Complex on the surface of an antigen-presenting cell (APC) leads to the spatial reorganization of the TCR and accessory receptors to form a specialized area of intimate contact between T cell and APC, known as the immunological synapse (IS), where signals are deciphered, coordinated, and integrated to promote T cell activation. With the discovery that an endosomal TCR pool contributes to IS assembly and function by undergoing polarized recycling to the IS, recent years have witnessed a shift from a plasma membrane-centric view of the IS to the vesicular trafficking events that occur at this location following the TCR-dependent translocation of the centrosome toward the synaptic membrane. Here we will summarize our current understanding of the trafficking pathways that are responsible for the steady delivery of endosomal TCRs, kinases, and adapters to the IS to sustain signaling, as well as of the endocytic pathways responsible for signal termination. We will also discuss recent evidence highlighting a role for endosomes in sustaining TCR signaling after its internalization at the IS and identifying the IS as a site of formation and release of extracellular vesicles that allow for transcellular communication with the APC.

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“…Tumor immune microenvironment was closely related to tumor prognosis, and NK cells and T cells are the main anti-tumor cells, which were associated with cancer immune evasion [ 47–49 ]. Among the 24 DEPs, IL33 and EHD3 were associated NK cell and played an important role in TCR-mediated T cell functions [ 50 , 51 ]. Edwin Wang et al proposed a cancer hallmark network framework for modeling genome sequencing data associated clinical phenotypes [ 52 , 53 ].…”

Section: Discussionmentioning

confidence: 99%

Development of cancer prognostic signature based on pan-cancer proteomics

et al. 2020

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Utilizing genomic data to predict cancer prognosis was insufficient. Proteomics can improve our understanding of the etiology and progression of cancer and improve the assessment of cancer prognosis. And the Clinical Proteomic Tumor Analysis Consortium (CPTAC) has generated extensive proteomics data of the vast majority of tumors. Based on CPTAC, we can perform a proteomic pan-carcinoma analysis. We collected the proteomics data and clinical features of cancer patients from CPTAC. Then, we screened 69 differentially expressed proteins (DEPs) with R software in five cancers: hepatocellular carcinoma (HCC), children’s brain tumor tissue consortium (CBTTC), clear cell renal cell carcinoma (CCRC), lung adenocarcinoma (LUAD) and uterine corpus endometrial carcinoma (UCEC). GO and KEGG analysis were performed to clarify the function of these proteins. We also identified their interactions. The DEPs-based prognostic model for predicting over survival was identified by least absolute shrinkage and selection operator (LASSO)-Cox regression model in training cohort. Then, we used the time-dependent receiver operating characteristics analysis to evaluate the ability of the prognostic model to predict overall survival and validated it in validation cohort. The results showed that the DEPs-based prognostic model could accurately and effectively predict the survival rate of most cancers.

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Role of the EHD Family of Endocytic Recycling Regulators for TCR Recycling and T Cell Function

Cited by 14 publications

References 79 publications

EHD1 and RUSC2 Control Basal Epidermal Growth Factor Receptor Cell Surface Expression and Recycling

EHD1 and RUSC2 Control Basal Epidermal Growth Factor Receptor Cell Surface Expression and Recycling

Orchestration of Immunological Synapse Assembly by Vesicular Trafficking

Development of cancer prognostic signature based on pan-cancer proteomics

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