MST1

Official Full Name

macrophage stimulating 1

Organism

Homo sapiens

GeneID

4485

Background

The protein encoded by this gene contains four kringle domains and a serine protease domain, similar to that found in hepatic growth factor. Despite the presence of the serine protease domain, the encoded protein may not have any proteolytic activity. The receptor for this protein is RON tyrosine kinase, which upon activation stimulates ciliary motility of ciliated epithelial lung cells. This protein is secreted and cleaved to form an alpha chain and a beta chain bridged by disulfide bonds. [provided by RefSeq, Jan 2010]

Synonyms

MSP; HGFL; NF15S2; D3F15S2; DNF15S2;

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Detailed Information

Mammalian sterile 20-like kinase 1 (MST1) is a homologous protein of yeast Ste20 kinase in mammals. MST1 has been extensively studied with its redefinition as a core component of the Hippo inhibition pathway in Drosophila. MST1 plays an important role in regulating embryonic growth and development, cell migration and differentiation, maintaining immune system stability, promoting apoptosis, and inhibiting tumor cell growth.

Biological Function of MST1

MST1 not only promotes the differentiation of tumor cells, but also regulates trophoblast differentiation and placental morphogenesis. Studies reported that MST1 also plays a regulatory role in cilia formation and ciliary basal localization, and this process is regulated by two separate signaling processes. MST1 plays a role in cell adhesion, endocytosis, and migration rate by mediating CCR7 (chemokine receptor 7) and DENND1C (differentially expressed in normal and neoplastic cells domain 1C). Decreased expression of MST1 inhibits phosphorylation of mature dendritic cells CCR7 and reduces cell migration by reducing the expression of Frizzled, myosin L light chain and myosin L light chain phosphatase. When stimulated, MST1 promotes phosphorylation of DENND1C (a guanine nucleotide conversion factor) in lymphocytes, thereby activating Rab13. Activated Rab13 and MST1 together promote the transfer of lymphocyte function-associated antigen 1 to the lymphocyte front, thereby increasing cell adhesion.

MST1 damages heart proteins by inhibiting autophagy. Activation of MST1 promotes the accumulation of p62 and the formation of aggregates in cardiomyocytes. MST1 exerts or promotes or inhibits autophagy by directly or indirectly phosphorylating autophagy-related proteins, the Atg8 family of proteins, providing opportunities for cardioprotection, tumor control, and immune regulation. Under the stimulation of apoptosis, MST1 can bind to GAPDH (glyceraldehyde-3-phosphate dehydrogenase), causing significant apoptosis of cardiomyocytes. The combination of MST1 with PCMT1 (protein L-isoaspartic acid (D-aspartate) o-methyltransferase 1) significantly attenuated the effect of cardiomyocytes on the apoptosis induced by hypoxia/reoxygenation. In all types of diabetes, MST1 is significantly activated, and activated MST1 induces apoptotic death by up-regulating BIM (BCL-2 homology-3 (BH3)-only) protein in beta cells, inducing disturbances in physiological functions of the human body.

Figure 1. Diabetic stimuli lead to activation of MST1, apoptosis and loss of function. (Ardestani, A. , et al. 2016)

MST1-related Signaling Pathway

Due to the homology of MST1 to Hippo, the classical pathway that starts with MST1 is called the Hippo signaling pathway. The upstream signal factors of MST1 are hMOB3 and mTORC2, and the basic substrates of MST1 include AKT, FOXO3, JNK, p38MAPK and hisone 2B. Mitotic activation of MST1 is the key to the smoothness of this signaling pathway. When MST1 division is inhibited, the Hippo pathway also becomes a pro-proliferative pathway. Studies have shown that activation of MST1 can be regulated not only by phosphorylation, but also by methylation, dimerization, promotion of acetylation of p53 (Lys382), and binding to cofactors.

Both mTOR and Hippo signaling pathways are major signaling pathways that regulate organ size and intracellular homeostasis. Chao et al. found that overexpression of MST1 and AKT in glioma cells negatively regulates the activity of AKT and mTOR, and ultimately inhibits cell proliferation and growth. In cardiomyocytes, mTORC2 phosphorylates the MST1 SARAH region Ser 438, thereby attenuating the homodimerization and kinase activity of MST1, ultimately achieving the protection of cardiac structure and function.

References:

Chao, Y. , Wang, Y. , Liu, X. , Ma, P. , Shi, Y. , & Gao, J. , et al. (2015). Mst1 regulates glioma cell proliferation via the akt/mtor signaling pathway. Journal of Neuro-Oncology, 121(2), 279-288.
Mukhopadhyay, N. K. , Kim, J. , You, S. , Morello, M. , Hager, M. H. , & Huang, W. C. , et al. (2014). Scaffold attachment factor b1 regulates the androgen receptor in concert with the growth inhibitory kinase mst1 and the methyltransferase ezh2. Oncogene, 33(25), 3235-3245.
Ardestani, A. , & Maedler, K. . (2016). Mst1: a promising therapeutic target to restore functional beta cell mass in diabetes. Diabetologia, 59(9), 1843-1849.

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