Iyer Deepak Narayanan, Faruq Omar, Zhang Lun, Rastgoo Nasrin, Liu Aijun, Chang Hong
Laboratory medicine program, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Canada.
Department of Hematology, Beijing Chaoyang Hospital, Capital University, Beijing, China.
Biomark Res. 2021 May 6;9(1):34. doi: 10.1186/s40364-021-00286-9.
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.
肉豆蔻酰化富含丙氨酸的蛋白激酶C底物（MARCKS）蛋白处于多个信号通路的交叉点，这些信号通路控制着正常和恶性细胞生理中的几个关键过程。作为蛋白激酶C的靶点，MARCKS在磷酸化的胞质形式和未磷酸化的质膜结合状态之间穿梭，同时调节多个分子伴侣，包括但不限于钙调蛋白、肌动蛋白、磷脂酰肌醇-4,5-二磷酸和磷脂酰肌醇-3激酶。由于这些相互作用，MARCKS直接或间接调节许多细胞功能，主要包括细胞骨架重组、膜运输、细胞分泌、炎症反应、细胞迁移和有丝分裂。最近的证据表明，MARCKS表达失调与血液系统癌症的发生和发展有关。虽然人们知道MARCKS会影响整体致癌作用，并在决定血癌的疾病结局中发挥作用，但我们仍处于解释MARCKS在肿瘤性疾病中的病理生理作用的早期阶段。关于MARCKS的磷酸化形式与未磷酸化形式在血癌中作为癌基因与肿瘤抑制基因的作用的矛盾报道，使情况更加复杂。在这篇综述中，我们将研究目前关于MARCKS在血液系统恶性肿瘤中的物理性质、分子网络、功能特性以及可能的致病作用的知识体系和不断发展的概念。重点还将放在理解MARCKS通过在诱导治疗耐药性中发挥关键作用来决定整体疾病预后的新机制上。此外，我们将强调MARCKS作为血癌中有价值的治疗靶点的重要性，并讨论现有策略应对MARCKS驱动的血癌的潜力。
