Structure and function of polarity‐inducing kinase family MARK/Par‐1 within the branch of AMPK/Snf1‐related kinases

Abstract

Kinases of the MARK/Par-1 family of S/T protein kinases are regulators of diverse cellular processes in Caenorhabditis elegans, Drosophila, yeast, and mammalian cells. They are involved in nematode embryogenesis, epithelial cell polarization, cell signaling, and neuronal differentiation. MARK phosphorylates microtubule-associated proteins such as tau and is a key regulator of microtubule-based intracellular transport. Hyperphosphorylation of tau causes defects in neuronal transport and may induce abnormal aggregation of tau in Alzheimer disease and other tauopathies. Recent high-resolution structure analysis of MARK fragments covering the kinase domain and accessory regulatory domains has revealed important details regarding the autoregulation of MARK, but their interpretation has remained controversial. Here we focus on the structural aspects of MARK activity and autoregulation. Comparison of the available MARK structures with related kinases of the AMPK family and with new structures of MARK isoforms (MARK2 and 3) reveals unexpected structural similarities between these kinases that may help to resolve the existing controversies.

Tau-induced neurodegeneration: mechanisms and targets

“…GSK-3 phosphorylation reduces the capability of tau to promote microtubule assembly in vitro and in cells [33,34] . together with the activity of other kinases such as CK1, Cdk5, and MARK, has the ability to signifi cantly affect tau phosphorylation and modulate its neuronal function [35][36][37][38] .Cyclin-dependent kinase 5 (Cdk5) is a member of the cyclin-dependent kinase family and, due to the expression of its regulator p35, its activity is highest in neurons.Cdk5/p35 plays a crucial role in brain development and function; Cdk5 complex p25 (a truncated form of p35) phosphorylates tau at epitopes similar to those phosphorylated during mitosis, suggesting that Cdk5/p25 is the cause of mitotic-like tau phosphorylation in the AD brain [24,39,40] .MARK (microtubule-associated protein-microtubule affinity regulating kinase) phosphorylates tau at specific sites (serines in KXGS motifs) in the microtubule-binding repeats and together with its homolog (Par-1) identifi ed in diverse species such as yeast (KIN1 and KIN2) and fruitfl ies, is involved in cell-cycle control, cellular polarization, neuronal migration, differentiation, and cell signaling [41] .They phosphorylate tau in its microtubule-binding domains, cause tau to lose its affi nity to bind microtubules, and the detached tau becomes aggregated [42] . Overexpression of the fl y homolog of MARK (dMARK) causes an increase in tau phosphorylation at Ser262/356 which increases tau toxicity [43,44] .…”

“…MARK (microtubule-associated protein-microtubule affinity regulating kinase) phosphorylates tau at specific sites (serines in KXGS motifs) in the microtubule-binding repeats and together with its homolog (Par-1) identifi ed in diverse species such as yeast (KIN1 and KIN2) and fruitfl ies, is involved in cell-cycle control, cellular polarization, neuronal migration, differentiation, and cell signaling [41] .…”

Role of the Centrosomal MARK4 Protein in Gliomagenesis

“…All MARK proteins have a very conserved structure, consisting of six sequence segments (Marx et al, 2010) (Figure 15):  the N-terminal header, whose role is unknown;  the catalytic or kinase domain, containing both the activation/inactivation loop (MARK kinases are in turn activated/inactivated by phosphorylation/dephosphorylation) and the catalytic loop, by which MARKs transfer a phosphate group to substrate proteins;  a linker, that is a highly and negatively charged motif resembling the common docking (CD) site in MAP kinases; it may bind interactors;  the UBA domain, a small globular domain with sequence homology to ubiquitinassociated proteins; it may exert an autoregulatory function through interaction with the catalytic domain;  a spacer, the most variable region among MARK members; it is probably important for regulating MARK activity since it holds phosphorylation sites;  the C-terminal tail, consisting of the kinase-associated (KA1) domain, whose function is still uncertain. It is characterized by a hydrophobic portion surrounded by positively charged residues, which may interact with negatively charged regions of cytoskeletal proteins, MARK catalytic domain or MARK CD domain (Tochio et al, 2006) with an inhibitory effect.…”

“…On the contrary, phosphorylation by the glycogen synthase kinase 3 (GSK3 ) on the serine residue in the activation loop, by aPKC (atypical protein kinase C) in the spacer region or by Pim1 kinase, down-regulates MARK activity (Matenia & Mandelkow, 2009;Timm et al, 2008). Finally, interaction between MARK catalytic domain and other proteins/MARK domains (such as 14-3-3 proteins, PAK5, MARK UBA and KA1 domains) inhibits MARK activity (Marx et al, 2010).…”

“…The two isoforms differ in the C-terminal tail, since MARK4L includes the kinase-associated 1 domain as the other MARK proteins, whereas MARK4S contains a domain with no homology to any known structure (Kato et al, 2001;Moroni et al, 2006) (Figure 16). Actually, MARK4 has less sequence homology in the Cterminus compared to the other MARKs; nevertheless MARK4L tail seems to fold in a similar shape, suggesting that the role of the C-terminal region may apply also to MARK4L (Marx et al, 2010).…”