EHD1 and RUSC2 control basal EGFR cell surface expression and recycling

Tom EC, Mushtaq I, Mohapatra BC, Luan H, Bhat AM, Zutshi N, Chakraborty S, Islam N, Arya P, Bielecki TA, Iseka FM, Bhattacharyya S, Cypher LR, Goetz BT, Negi SK, Storck MD, Rana S, Barnekow A, Singh PK, Ying G, Guda B, Natarajan A, Band V, Band H

Abstract

ABSTRACT Epidermal growth factor receptor (EGFR) is a prototype receptor tyrosinekinase and an oncogene in many solid tumors. Cell surface display of EGFR isessential for cellular responses to its ligands. While postactivation endocytic traffickingof 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 endocyticregulator 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 theGolgi compartment. Inducible EHD1 knockdown reduced the cell surface EGFR expressionwith accumulation at the Golgi compartment, a phenotype rescued by exogenousEHD1. RUSC2 knockdown phenocopied the EHD1 depletion effects. EHD1or RUSC2 depletion impaired the EGF-induced cell proliferation, demonstrating thatthe novel, EHD1- and RUSC2-dependent transport of unstimulated EGFR from theGolgi compartment to the cell surface that we describe is functionally important,with implications for physiologic and oncogenic roles of EGFR and targeted cancertherapies.