Macrophage-Stimulating Protein Receptor

The tyrosine kinase Ron, receptor for MSP (macrophage-stimulating protein), displays several serine residues of unknown functions. Using [32P]H3PO4 metabolic labelling, we found that Ron is serine-phosphorylated and dephosphorylated in vitro by PP1 (protein phosphatase 1). PP1 associates with Ron obtained from cells of different origins. The association is stimulated by MSP or serum and is prevented by wortmannin, an inhibitor of the Akt/PKB (protein serine/threonine kinase B) pathway. Akt/PKB phosphorylates Ron Ser-1394, thus providing a docking site for 14-3-3 (scaffold proteins binding to phosphoserine/phosphothreonine-containing sequences). In living cells, PP1 binds to the Ron mutant S1394A, but the association is no longer regulated by serum, MSP or wortmannin. The role of PP1 association with Ron is highlighted by (1) Ser-1394 dephosphorylation by PP1 in vitro and in living cells, (2) loss of 14-3-3 association with Ron after Ser-1394 dephosphorylation by PP1 in vitro and (3) an increase in 14-3-3 association after PP1 inactivation in living cells. These results suggest that PP1 can modulate the downstream Ron signalling generated by MSP via Akt/PKB and 14-3-3 binding. This is the first report on ligand-regulated association of PP1 with a growth factor receptor.

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Therapeutic Implications of a Human Neutralizing Antibody to the Macrophage-Stimulating Protein Receptor Tyrosine Kinase (RON), a c-MET Family Member

Cancer Research ◽

10.1158/0008-5472.can-06-0283 ◽

2006 ◽

Vol 66 (18) ◽

pp. 9162-9170 ◽

Cited By ~ 92

Author(s):

Jennifer M. O'Toole ◽

Karen E. Rabenau ◽

Kerri Burns ◽

Dan Lu ◽

Venkat Mangalampalli ◽

...

Keyword(s):

Tyrosine Kinase ◽

Family Member ◽

Receptor Tyrosine Kinase ◽

Neutralizing Antibody ◽

Macrophage Stimulating Protein ◽

Therapeutic Implications ◽

Protein Receptor

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AMP-activated protein kinase regulates alternative pre-mRNA splicing by phosphorylation of SRSF1

Biochemical Journal ◽

10.1042/bcj20190894 ◽

2020 ◽

Vol 477 (12) ◽

pp. 2237-2248

Author(s):

Eri Matsumoto ◽

Kaho Akiyama ◽

Takuya Saito ◽

Yu Matsumoto ◽

Ken-Ichi Kobayashi ◽

...

Keyword(s):

Protein Kinase ◽

Energy Homeostasis ◽

Mrna Splicing ◽

Splicing Factor ◽

Rna Recognition Motif ◽

Rna Sequences ◽

Macrophage Stimulating Protein ◽

Protein Receptor ◽

Amp Activated Protein Kinase ◽

Splicing Factor 1

AMP-activated protein kinase (AMPK) regulates cellular energy homeostasis by inhibiting anabolic processes and activating catabolic processes. Recent studies have demonstrated that metformin, which is an AMPK activator, modifies alternative precursor mRNA (pre-mRNA) splicing. However, no direct substrate of AMPK for alternative pre-mRNA splicing has been reported. In the present study, we identified the splicing factor serine/arginine-rich splicing factor 1 (SRSF1) as a novel AMPK substrate. AMPK directly phosphorylated SRSF1 at Ser133 in an RNA recognition motif. Ser133 phosphorylation suppressed the interaction between SRSF1 and specific RNA sequences without altering the subcellular localization of SRSF1. Moreover, AMPK regulated the SRSF1-mediated alternative pre-mRNA splicing of Ron, which is a macrophage-stimulating protein receptor, by suppressing its interaction with exon 12 of Ron pre-mRNA. The findings of this study revealed that the AMPK-dependent phosphorylation of SRSF1 at Ser133 inhibited the ability of SRSF1 to bind RNA and regulated alternative pre-mRNA splicing.

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