Differential regulation of actin microfilaments by human MICAL proteins

Abstract

SummaryThe Drosophila melanogaster MICAL protein is essential for the neuronal growth cone machinery that functions through plexin-and semaphorin-mediated axonal signaling. Drosophila MICAL is also involved in regulating myofilament organization and synaptic structures, and serves as an actin disassembly factor downstream of plexin-mediated axonal repulsion. In mammalian cells there are three known isoforms, MICAL1, MICAL2 and MICAL3, as well as the MICAL-like proteins MICAL-L1 and MICAL-L2, but little is known of their function, and information comes almost exclusively from neural cells. In this study we show that in non-neural cells human MICALs are required for normal actin organization, and all three MICALs regulate actin stress fibers. Moreover, we provide evidence that the generation of reactive oxygen species by MICAL proteins is crucial for their actin-regulatory function. However, although MICAL1 is auto-inhibited by its C-terminal coiled-coil region, MICAL2 remains constitutively active and affects stress fibers. These data suggest differential but complementary roles for MICAL1 and MICAL2 in actin microfilament regulation.

Identification of a Dithiol-disulfide Switch in Collapsin Response Mediator Protein 2 (CRMP2) That Is Toggled in a Model of Neuronal Differentiation

“…Refs. [43][44][45]. For instance, a transcript variant (TXNRD1_v3) of the selenoprotein thioredoxin reductase 1 encodes an atypical N-terminal Grx domain.…”

MICAL1 facilitates breast cancer cell proliferation via ROS‐sensitive ERK/cyclin D pathway

“…They are widely expressed in nervous system and other tissues, including endothelial cells and cancer cells such as melanoma and HeLa cells 4, 5, 6, 7. Although MICAL family is identified as MICAL (1‐3) and MICAL‐like (‐L1, ‐L2) forms in mammals, its main functions were studied mostly in Drosophila 1, 3, 8.…”

Emerging roles of MICAL family proteins – from actin oxidation to membrane trafficking during cytokinesis

“…Several previous studies have demonstrated that the full-length MICAL1 is catalytically inactive as it adopts an auto-inhibitory state in the absence of stimuli (Giridharan et al, 2012b;Schmidt et al, 2008). The N-and C-terminal regions of the protein have been shown to physically interact and this likely inhibits the enzymatic activity (Schmidt et al, 2008).…”

“…Uncontrolled activation of MICAL family members leads to almost complete depolymerization of all F-actin pools in cells (Giridharan et al, 2012b;Grigoriev et al, 2011;Hung et al, 2010), implying that MICAL-mediated enzymatic activity and localization must be tightly regulated. In this section, we discuss the most recent findings we and other have obtained with regard to the localization and activation of MICALs, in particular the emerging roles of Rab GTPases in both processes.…”

“…2). For example, MICAL proteins are required for several aspects of neuronal biology (Beuchle et al, 2007;Bron et al, 2007;Hung et al, 2013Hung et al, , 2010Kirilly et al, 2009;Lundquist et al, 2014;Luo et al, 2011;Morinaka et al, 2011;Pasterkamp et al, 2006;Schmidt et al, 2008;Terman et al, 2002;Van Battum et al, 2014), cell viability (Ashida et al, 2006;Loria et al, 2015;Zhou et al, 2011), cancer (Deng et al, 2016;Loria et al, 2015;Mariotti et al, 2016), immunity (Lee et al, 2013), skeletal muscle morphology and function (Beuchle et al, 2007;Hung et al, 2013), cardiovascular integrity , bristle development (Hung et al, 2011(Hung et al, , 2013, cell shape (Aggarwal et al, 2015;Giridharan et al, 2012b), membrane trafficking (Bachmann-Gagescu et al, 2015;Grigoriev et al, 2011) and regulation of nuclear actin (Lundquist et al, 2014). The newly described roles of MICAL family members in cytokinesis will be discussed in detail below.…”