Pathophysiological roles of myristoylated alanine-rich C-kinase substrate (MARCKS) in hematological malignancies

Abstract

The myristoylated alanine-rich C-kinase substrate (MARCKS) protein has been at the crossroads of multiple signaling pathways that govern several critical operations in normal and malignant cellular physiology. Functioning as a target of protein kinase C, MARCKS shuttles between the phosphorylated cytosolic form and the unphosphorylated plasma membrane-bound states whilst regulating several molecular partners including, but not limited to calmodulin, actin, phosphatidylinositol-4,5-bisphosphate, and phosphoinositide-3-kinase. As a result of these interactions, MARCKS directly or indirectly modulates a host of cellular functions, primarily including cytoskeletal reorganization, membrane trafficking, cell secretion, inflammatory response, cell migration, and mitosis. Recent evidence indicates that dysregulated expression of MARCKS is associated with the development and progression of hematological cancers. While it is understood that MARCKS impacts the overall carcinogenesis as well as plays a part in determining the disease outcome in blood cancers, we are still at an early stage of interpreting the pathophysiological roles of MARCKS in neoplastic disease. The situation is further complicated by contradictory reports regarding the role of phosphorylated versus an unphosphorylated form of MARCKS as an oncogene versus tumor suppressor in blood cancers. In this review, we will investigate the current body of knowledge and evolving concepts of the physical properties, molecular network, functional attributes, and the likely pathogenic roles of MARCKS in hematological malignancies. Key emphasis will also be laid upon understanding the novel mechanisms by which MARCKS determines the overall disease prognosis by playing a vital role in the induction of therapeutic resistance. Additionally, we will highlight the importance of MARCKS as a valuable therapeutic target in blood cancers and will discuss the potential of existing strategies available to tackle MARCKS-driven blood cancers.

Keywords: Drug resistance; Hematological cancers; MARCKS; Targeted therapy.

Fig. 1

MARCKS protein structure. (a) The image was created from the protein data bank (PDB) entries 1IWQ [22] and adapted using PyMOL Version 2.2 [23]. (b) Linear representation of the MARCKS protein containing the Myristoyl Domain, N-terminal Domain, MH2 domain, a phosphorylation site domain (PSD; also known as the effector domain (ED)), and C-terminal Domain (c) Schematic representation of the MARCKS protein bound to the plasma membrane by the myristoylated N-terminal domain. Other structural elements include an MH2 domain and the ED. The ED (amino acids: 152–176) can be phosphorylated by PKC at three or four serine residues (marked in red) or can be bound to CaM and actin. The ED also electrostatically interacts with the plasma membrane and provides additional support to the N-terminal myristate moiety-mediated binding of MARCKS to the phospholipid bilayer of the membrane

Fig. 2

Molecular partners of MARCKS. While MARCKS shuttles between the phosphorylation-dependent or calcium-dependent activation pathways, it directly or indirectly modulates the activity of several key members within multiple signaling networks. Shown are the major molecular partners that contribute to the functional relevance of MARCKS

Fig. 3

Strategies to target MARCKS signaling. Schematic depicting the current approaches available to target MARCKS signaling in cancer. Indirect targeting includes inhibitors for PKC and NADPH oxidase (NOX) which induce the phosphorylation of MARCKS. Direct targeting of MARCKS can be performed using small RNAs, peptidomimetics, or alternative strategies as a single agent or in combination with traditional chemotherapy and/or radiotherapy