Emerging Roles of Ephexins in Physiology and Disease

Abstract

Dbl (B-cell lymphoma)-related guanine nucleotide exchange factors (GEFs), the largest family of GEFs, are directly responsible for the activation of Rho family GTPases and essential for a number of cellular events such as proliferation, differentiation and movement. The members of the Ephexin (Eph-interacting exchange protein) family, a subgroup of Dbl GEFs, initially were named for their interaction with Eph receptors and sequence homology with Ephexin1. Although the first Ephexin was identified about two decades ago, their functions in physiological and pathological contexts and regulatory mechanisms remained elusive until recently. Ephexins are now considered as GEFs that can activate Rho GTPases such as RhoA, Rac, Cdc42, and RhoG. Moreover, Ephexins have been shown to have pivotal roles in neural development, tumorigenesis, and efferocytosis. In this review, we discuss the known and proposed functions of Ephexins in physiological and pathological contexts, as well as their regulatory mechanisms.

Double inhibition and activation mechanisms of Ephexin family RhoGEFs

“…Eph-interacting exchange protein (Ephexin) family RhoGEFs activate Rho GTPases, including RhoA, Rac, Cdc42, and RhoG (8). This family consists of five known members in most vertebrate species (Ephexin1 to -5).…”

“…This family consists of five known members in most vertebrate species (Ephexin1 to -5). A common feature of the Ephexin family proteins is that they all associate with and act downstream of Eph receptors, the largest subfamily of tyrosine kinase receptors that are activated by Ephrins and participate in various cellular processes (8)(9)(10)(11). Specifically, Ephexin1 (also known as NGEF or ARHGEF27) regulates axon growth cone dynamics and spine morphogenesis via binding to EphA4 and activation of RhoA (9,(12)(13)(14).…”

“…Ephexin5 (also known as Vsm-RhoGEF or ARHGEF15) functions together with EphB2 to regulate excitatory synapse development (17). Notably, the biological functions of Ephexin2 and Ephexin3 remain elusive although they are known to activate RhoA (8). Therefore, the Ephexin family RhoGEFs serve as the regulatory hubs that link Ephrin-Eph signaling with cytoskeletal dynamics through spatiotemporal regulation of Rho GTPases.…”

FYN is required for ARHGEF16 to promote proliferation and migration in colon cancer cells

“…Ephrin signaling plays a key role in cellular repulsion, attraction, and migration by controlling local cytoskeletal dynamics through Ephexin proteins and Rho GTPases 8,12 . Dysregulation of ARHGEF16 contributes to carcinogenesis and tumor progression 13,21 . However, how ARH-GEF16 is regulated in response to the progression of colon cancer remains poorly understood.…”

“…(ARHGEF5/TIM1), Ephexin4 (ARH GEF16), and Ephexin5 (ARHGEF15/Vsm-RhoGEF) 9,21,[29][30][31][32] . It has been reported that Ephexin1 and Ephexin5 are phosphorylated by Src or Eph receptors but not ARH-GEF16 21,29,33 . Here, we showed that FYN stabilized ARH-GEF16 by promoting ARHGEF16 phosphorylation in a manner dependent on FYN.…”