Date Published: June 1, 2018
Publisher: JKL International LLC
Author(s): Sheng Chen, Yuanjian Fang, Shenbin Xu, Cesar Reis, Jianmin Zhang.
Mammalian Sterile20-like (MST) kinases are located upstream in the mitogen-activated protein kinase pathway, and play an important role in cell proliferation, differentiation, renewal, polarization and migration. Generally, five MST kinases exist in mammalian signal transduction pathways, including MST1, MST2, MST3, MST4 and YSK1. The central nervous system (CNS) is a sophisticated entity that takes charge of information reception, integration and response. Recently, accumulating evidence proposes that MST kinases are critical in the development of disease in different systems involving the CNS. In this review, we summarized the signal transduction pathways and interacting proteins of MST kinases. The potential biological function of each MST kinase and the commonly reported MST-related diseases in the neural system are also reviewed. Further investigation of MST kinases and their interaction with CNS diseases would provide the medical community with new therapeutic targets for human diseases.
In general, there are five MST kinases including MST1 or serine/threonine-protein kinase 4 (STK4), MST2 (STK3), MST3 (STK24), MST4 (STK26), and YSK1 (STK25) that exist in mammalian signal transduction pathways . MST1 and MST2 (Hippo pathway in Drosophila) are considered as the members of germinal center kinase (GCK) II subfamily. The MST3, MST4, and YSK1 are divided into the GCKIII subfamily [7, 27]. With assistance from the sequence analysis and function data, it was accepted that the yeast kinases Cdc15 and Sid1 are most matched to MST1 and MST2, while Kic1 and Nak1 in yeast are most matched to the MST3, MST4, and YSK1 . The biological functions of these kinases include their roles in signal transduction pathways which help maintain cell homeostasis. Here we introduced these kinases in two parts: MST1 and MST2 (Fig. 1); MST3, MST4 and YSK1 (Fig. 2).
With the assistance of cofactor WW-domain scaffolding protein WW45 (Sav in Drosophila), MST1/2 binds and phosphorylates the downstream Nuclear Dbf2-related (NDR) family kinases and Large tumor suppressor (Lats1/2, as Warts in Drosophila), through interaction with SARAH domains . Meanwhile, phosphorylation of Mps one binder kinase activator-like 1 (Mob1, Mats in Drosophila) a/b by MST1/2 promotes the integration between Mob1a/b and Lats1/2 and actives the Lats1/2 . With the induction of Lats1/2, two intranuclear transcriptional regulators, Yes-associated protein (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ), which are similar as Yki in Drosophila, interact with 14-3-3 proteins and subsequently lose their function in cytoplasm . This mechanism negatively attenuates transcription activity from losing interaction between YAP/TAZ and their target genes. Intranuclear YAP interacts with the TEAD1-4 transcription factor to stimulate cell proliferation and against the cellular death . Thus, the mammalian Hippo pathway avoids excessive proliferation and organ overgrowth in stem cells [31, 32]. A recent study found that MST1 and MST2 signal also inhibits YAP function by suppressing GA-binding protein (GABP) transcriptional activity . Additionally, the Hippo pathway can regulate polarization of the F-actin cytoskeleton in epithelial cells and migrating border cells [34, 35]. This mechanism was demonstrated in the Drosophila through inhibiting the Ena/Capping protein system instead of Yki [34, 35].
Compared to the MST1 and MST2 kinases, less is known about MST3, MST4, and YSK1 kinases. The MST3, MST4, and YSK1 kinases play essential roles in regulation of cell polarity, cell adhesion, and cell migration. Normally, with assistance of different Golgi matrix proteins, these three kinases are recruited to the Golgi apparatus [11, 42, 43]. GM130 may be the common protein of MST4 and YSK1 that help target the Golgi apparatus. MST3 localize on the Golgi through interaction with Striatin proteins [11, 43, 44], and this interactions inactives MST3 and MST4. In contrast, YSK1 binding the GM130 may play a positive role on Golgi apparatus. The biochemical screening identifies YSK1 as locating to the Golgi apparatus via a special substrate, 14-3-3 proteins. This link causes potential concern for protein transport, cell polarity, and cell adhesion. The adaptor proteins, cerebral cavernous malformation 3 (CCM3) protein or Mo25 can induce the movement of MST3 and MST4 from the Golgi apparatus to the plasma membrane. Active MST3 and MST4 promote the co-localization of the actomyosin with the help of Ezrin protein [26, 45]. In addition, MST3 directly phosphorylates the downstream protein-tyrosine phosphatase (PTP)-PEST and inhibits the activity of tyrosine phosphatase activity on PTP-PEST. This reaction inhibits the PTP-PEST dependent paxillin phosphorylation and consequently attenuates cell migration . The PTP-PEST is involved in actin cytoskeleton regulation and actively contributes to the cellular apoptotic response . As in the pathway of MST1 and MST2 on Lats, MST3 can phosphorylate and activate the NDR protein kinases at the site of Thr442/Thr444. It also regulates cell cycle progression and morphology control . However, evidence of MST4 or YSK1 directly phosphorylating NDR protein kinases in mammalian systems remains unclear .
Regulation of MST kinases is complicated and the current studies on regulatory mechanisms are not well understood. Here we conclude with several potential regulator signals of MST kinases (Fig. 3 and Fig. 4)
MST kinases exist in the mammalian cellular signal transductions to control cell homeostasis and survival involving cell apoptosis, differentiation, migration, and transformation . Evidence showed MST kinases have essential roles in the immune system [62, 63], digestive system [20, 64], cardiovascular system [65, 66], respiratory system  and CNS. We give an overview of MST kinases and their various roles in CNS function (Table 1).
As discussed above, the MST1/2-Lats-YAP/TAZ signaling pathway has potent effects on regulating cell proliferation, and was accepted as a potential mechanism of tumor growth. The evidence shows that down-regulated MST1 expression can be a tumor growth marker of colorectal cancer or lymphoma/leukemia[80, 81]. Decreased Lats level can be observed in the breast cancers and mesotheliomas [82, 83]. While up-regulated YAP/TAZ expression has also been demonstrated taking parts in cancer development, such as lung cancer , hepatocellular carcinoma , colorectal cancer , pancreatic ductal, medullablastoma  and neurofibromatosis type2 . Meanwhile, this phenomenon was also detected in cerebral malignant tumor at the mRNA and protein levels. Moreover, they found new evidence that YAP/TAZ can abnormally activate the target gene, BIRC5, accompanied with down-regulation of LATS1/2, in turn simulating aberrant cell growth and neoplasia in glioblastoma . However, the upstream regulator of MST1/2-Lats-YAP/TAZ signaling pathway remains unknown in their study. MicroRNAs (miRNAs) are critical components in human tumorigenesis with the assistance of their mRNA 3′ untranslated regions [89, 90]. Recently, a study found that miR-130b, situated upstream of MST1/2-Lats-YAP/TAZ, was substantially overexpressed in human glioblastoma growth. Hyperactivation of miR-130b directly suppressed MST1 activity, further leading to YAP/TAZ activation .
Cerebrovascular diseases include cerebral hemorrhage, ischemic, arterial or venous malformations, or other vascular lesions . Death from stoke is three times more likely than death from coronary cardiovascular diseases in China . The most common disease concerning MST kinases is CCM, which can change neurological function via hemorrhage, vascular steal, venous congestion, or compression effect on normal brain tissue . Disorders in the signaling pathways of MST3, MST4, and STK25 are the widely accepted factor in CCM pathology [18, 104]. The CCM gene family includes CCM1, CCM2, and CCM3. The clinical manifestations of patients suffering genetic mutations of these three genes are similar, suggesting a common pathway integrated with their expression . Previous studies demonstrated that STK24 and STK25 interact with CCM3, but only STK25 has the ability to phosphorylate CCM3 [75, 106]. STK25 forms a protein complex with CCM2 . However, the specific mechanism and potential relationship between STK25, CCM2, and CCM3 remains vague. This link between CCM2, CCM3, and STK25 can be the essential part of signaling pathways in CCM pathogenesis. A recent study proposed that STK24 and STK25 control endothelial cell-cell junctions through directly activating ERM family protein, which negatively regulates Rho. They speculated that the CCM3/STK signaling may share a common pathway with STK/ERM/Rho signaling to regulate epithelial and endothelial cell junctions. This is essential in cardiovascular development and diseases such as CCM . While it is obvious that GCKIII family proteins widely participate in endothelial pathologies, more work is required to effectively elaborate on the exact relationship between GCKIII family proteins and CCMs.
MST kinases are involved in neurodegenerative diseases including Alzheimer’s disease (AD) and Amyotrophic lateral sclerosis (ALS). AD is the most common neurodegenerative disease. However, the mechanisms behind AD remain unclear [122, 123]. Excessive binding protein Tau phosphorylation is wildly accepted as a feature of AD, Parkinson’s, and Frontal Temporal Lobe Dementia [124, 125]. Docking protein Dab1 deficiency in Reelin signaling pathway can lead to Tau hyperphosphorylation. However, the physiological function of STK25 (performs neuronal polarization regulation and Golgi morphology) was found to have the ability to defend against the Dab1 effect in development of AD in rat model, demonstrating the anti-AD effect of STK25 . Thus, the investigation of STK25 in AD is a topic of interest in AD treatment.
Spinal cord injury is a devastating neurological diseases associated with high morbidity and functional impairments impacting quality of life [139-141]. MST3b is activated by neurotrophic factors and promotes axon outgrowth in damaged adult optic nerve and radial nerve [14, 72]. Moreover, it was found that Mst3b also plays an important role in injured spinal cord neurons. Increased MST3b levels can facilitate axonal regeneration of spinal cord neurons in vivo and in vitro. MST3b interacts with small G protein Ras and MAPK kinase, promoting down-stream signaling pathways, including P42/44MAPK and LIMK/Cofilin signaling pathway, which further modulates actin cytoskeleton, resulting in axon regeneration in spinal cord neurons .
MST kinases are an essential part the signaling transduction pathways, maintaining numerous biological functions, such as controlling cell growth, cell migration, cell polarity and cell apoptosis. The regulation of MST kinases is complicated and current studies on the regulatory mechanisms are not well understood. Accumulating evidence suggests MST kinases have essential roles in different body systems. They are also important to the CNS when it comes to biological function and development of disease. Increasing investigation and understanding of MST signaling pathways including regulatory and pathological processes of MST kinases and their role in the CNS could provide the research and medical community with new therapeutic targets for human diseases.