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.

Mammalian D‐cysteine: A novel regulator of neural progenitor cell proliferation

“…Phosphorylation of MARCKS may in turn affect actin polymerization and cytoskeleton rearrangement affecting neuronal migration (Figure 4C). [ 73 ] Future studies may determine D‐cysteine binding regions in MARCKS to clarify the structural significance of this interaction due to the importance of MARCKS in regenerative medicine. [ 30 ]…”

“…Phosphorylated FoxO (inactive) translocates to the cytoplasm bound to 14-3-3. [72,73] Phosphorylation of MARCKS by PKC leads to inhibition of AKT activation. [74] Other targets of AKT include GSK3b, S6K, 4E-BP1 and caspase.…”

The Profile of MicroRNA Expression and Potential Role in the Regulation of Drug-Resistant Genes in Doxorubicin and Topotecan Resistant Ovarian Cancer Cell Lines

“…As we did not describe it previously, this time we focused in detail on the physiological and pathological roles of this protein. MARCKS is the main target of protein kinase C. In the unphosphorylated form, it is bound to the plasma membrane, and after phosphorylation shuttling to the cytoplasm, it regulates different cellular processes, such as cytoskeletal reorganization, membrane trafficking, cell secretion, inflammatory response, cell migration, and mitosis [ 103 , 104 ]. It has been reported that MARCKS is associated with the development and progression of hematological cancers [ 103 ].…”

“…MARCKS is the main target of protein kinase C. In the unphosphorylated form, it is bound to the plasma membrane, and after phosphorylation shuttling to the cytoplasm, it regulates different cellular processes, such as cytoskeletal reorganization, membrane trafficking, cell secretion, inflammatory response, cell migration, and mitosis [ 103 , 104 ]. It has been reported that MARCKS is associated with the development and progression of hematological cancers [ 103 ]. The role of MARCKS in tumorigenesis, metastasis, and resistance to anti-cancer therapies of other cancers has also been described [ 104 ].…”

MARCKS Is an Essential Regulator of Reactive Oxygen Species Production in the Monocytic Cell Type

“…In consequence, MARCKS is involved in the regulation of a variety of cellular processes such as cytoskeletal reorganization, mitosis, adhesion, migration, vesicle trafficking, secretion, and signal transduction [ 10 ]. Accordingly, disturbances in MARCKS level or function are associated with numerous pathophysiological conditions [ 11 ], e.g., pulmonary [ 12 ] or neuronal diseases [ 13 ], cancer and metastasis [ 1 , 14 ], or fibrosis [ 15 ].…”