MICAL-Family Proteins: Complex Regulators of the Actin Cytoskeleton

Abstract

Significance: The molecules interacting with CasL (MICAL) family members participate in a multitude of activities, including axonal growth cone repulsion, membrane trafficking, apoptosis, and bristle development in flies. An interesting feature of MICAL proteins is the presence of an N-terminal flavo-mono-oxygenase domain. This mono-oxygenase domain generates redox potential with which MICALs can either oxidize proteins or produce reactive oxygen species (ROS). Actin is one such protein that is affected by MICAL function, leading to dramatic cytoskeletal rearrangements. This review describes the MICAL-family members, and discusses their mechanisms of actin-binding and regulation of actin cytoskeleton organization. Recent Advances: Recent studies show that MICALs directly induce oxidation of actin molecules, leading to actin depolymerization. ROS production by MICALs also causes oxidation of collapsin response mediator protein-2, a microtubule assembly promoter, which subsequently undergoes phosphorylation. Critical Issues: MICAL proteins oxidize proteins through two mechanisms: either directly by oxidizing methionine residues or indirectly via the production of ROS. It remains unclear whether MICAL proteins employ both mechanisms or whether the activity of MICALfamily proteins might vary with different substrates. Future Directions: The identification of additional substrates oxidized by MICAL will shed new light on MICAL protein function. Additional directions include expanding studies toward the MICAL-like homologs that lack flavin adenine dinucleotide domains and oxidation activity.

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

“…Normally, MICAL family members have four conserved domains: N‐terminal flavin adenine dinucleotide (FAD) binding domain, Lin11, Isl‐1 and Mec‐3 (LIM) domain, calponin homology (CH) domain and C‐terminal coiled‐coil (CC) domain. FAD domain contains flavin mono‐oxygenase activity and is responsible for majority of MICAL1's function 9. Recently, overexpression of MICAL2 and MICAL‐L2, the other members of MICAL family, has been confirmed to be related to multiple invasive phenotype of cancer cells such as increased motility, proliferation, as well as inducing epithelial‐to‐mesenchymal transition (EMT) 10, 11.…”

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

“…We will also review the physiological roles of this emerging class of enzymes on actin-dependent functions, with a special emphasis on their recently demonstrated involvement in cytokinesis (Frémont et al, 2017;Liu et al, 2016;Reinecke et al, 2015). Other biological aspects of the MICAL family are also mentioned briefly and are covered in detail in excellent recent reviews (Giridharan and Caplan, 2014;Wilson et al, 2016).…”

“…1). Members of the MICAL family are multidomain proteins that contain an N-terminal flavoprotein monooxygenase (MO) domain that is essential for its actin-depolymerizing activity (Alqassim et al, 2016;Nadella et al, 2005;Siebold et al, 2005) (see below), a calponin homology (CH) domain typical of actin-binding proteins, a LIM domain (for 'Lin-11, Isl-1 and Mec-3'); and a Rab-binding domain (RBD) with motifs initially proposed to form a coiled-coil domain (Giridharan and Caplan, 2014;Wilson et al, 2016) (Fig. 1).…”

“…MICAL-like proteins have been implicated so far in the endocytic pathway (Abou-Zeid et al, 2011;Bahl et al, 2016;Cai et al, 2014;Giridharan and Caplan, 2014;Rahajeng et al, 2010Rahajeng et al, , 2012Reinecke et al, 2015;Sharma et al, 2010Sharma et al, , 2009Terai et al, 2006), exocytosis , phagosomal maturation (Dumas et al, 2015), synaptic development (Nahm et al, 2016), neurite outgrowth (Kobayashi et al, 2014a,b;Kobayashi and Fukuda, 2013), cell division (Reinecke et al, 2015), cell shape (Kanda et al, 2008;Sakane et al, 2012Sakane et al, , 2013, cell junction formation Sakane et al, 2012;Yamamura et al, 2008), cell migration (Sakane et al, 2016) and cancer development (Ioannou et al, 2015;Zhu et al, 2015). As MICAL-like proteins lack the N-terminal monooxygenase domain involved in F-actin oxidation and disassembly, we will essentially focus this Commentary on MICAL proteins.…”

“…As MICAL-like proteins lack the N-terminal monooxygenase domain involved in F-actin oxidation and disassembly, we will essentially focus this Commentary on MICAL proteins. More details about MICAL-like functions can be found in previous reviews (Giridharan and Caplan, 2014;Rahajeng et al, 2010).…”