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. 2025 Aug;319(Pt 4):145651.
doi: 10.1016/j.ijbiomac.2025.145651. Epub 2025 Jun 30.

Constitutive expression of a 34 kDa Mst1 fragment in the forebrain distinct from the caspase 3-cleaved isoform

Farooqahmed S Kittur  1 , Qaisar Mahmood  2 , Mythili Saravanan  3 , Qing Cheng  4 , Jiahua Xie  5
Affiliations

Constitutive expression of a 34 kDa Mst1 fragment in the forebrain distinct from the caspase 3-cleaved isoform

Farooqahmed S Kittur et al. Int J Biol Macromol. 2025 Aug.

Abstract

Mammalian sterile 20-like kinase 1 (Mst1), a ubiquitously expressed 60 kDa serine/threonine kinase, plays crucial roles in various cellular processes. Mst1 is activated by autophosphorylation at Thr183 and caspase 3-mediated cleavage, producing a catalytically active 36/37 kDa (or, in some studies, a 34 kDa) fragment under apoptotic conditions. However, whether the 34 and 36/37 kDa fragments observed in different studies are identical remains unclear, given their similar sizes and the specific detection of a 34 kDa fragment in normal mouse liver and intestinal epithelial cells. This study aimed to resolve this question. Here, we demonstrate that 34 and 36/37 kDa fragments are distinct and coexist in staurosporine-treated neuronal cells. Peptide mapping revealed that the 34 kDa band corresponds to Mst1 amino acids 1-301, in contrast to the caspase 3-cleaved 36/37 kDa fragment, which comprises amino acids 1-326. The 34 kDa fragment is expressed endogenously in the forebrain under physiological conditions, lacks Thr183 phosphorylation, and shows higher expression in brain regions such as the cortex, striatum, and hippocampus, while being absent in the brainstem and cerebellum. However, the 34 kDa fragment produced in Escherichia coli exhibits kinase activity comparable to that of the 37 kDa fragment. Furthermore, incubation of recombinant full-length Mst1 with brain extracts resulted in the production of a 34 kDa fragment, suggesting a potential proteolytic mechanism for its generation. Collectively, these findings prove that the 34 kD Mst1 present in normal brain tissues and neuronal cells is distinct from the 36/37 kD Mst1 fragment produced by caspase 3 cleavage under apoptotic conditions. Further investigations are necessary to elucidate its function.

Keywords: 34 kDa Mst1fragment; 36/37 kDa Mst1 fragment; Brain regions; Kinase activity; Mammalian sterile 20-like kinase 1; Organs; Phosphorylation.

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Conflict of interest statement

Declaration of competing interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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