Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB

Area of Science:

• Molecular Biology
• Cell Signaling
• Biochemistry

Background:

• Mitogen- and stress-activated protein kinases (MSKs) play crucial roles in cellular signaling pathways.
• Understanding the specific kinases involved in growth factor and stress responses is essential for elucidating cellular regulation.

Purpose of the Study:

• To identify and characterize a novel protein kinase involved in both mitogenic and stress-induced signaling.
• To investigate the role of this kinase in the activation of transcription factors like CREB.

Main Methods:

• Identification and in vitro activation assays of the novel kinase, MSK1.
• Stimulation of endogenous MSK1 in various cell lines using growth factors, phorbol esters, UV radiation, and chemical stressors.
• Inhibition studies using specific pathway inhibitors (PD 98059, SB 203580) to dissect signaling pathways.
• Nuclear localization studies and in vitro phosphorylation assays of CREB.

Main Results:

• A novel kinase, MSK1, possessing two kinase domains, was identified.
• MSK1 activation was observed in response to both growth factor/phorbol ester stimulation and various stress conditions.
• Inhibitor studies indicated distinct pathways for growth factor-induced (MAPK cascade) and stress-induced (SAPK2/p38) MSK1 activation.
• MSK1 is a nuclear protein that efficiently phosphorylates CREB at Ser133.
• MSK1 activation and CREB/ATF1 phosphorylation were similarly affected by pathway inhibitors, implicating MSK1 in CREB activation.

Conclusions:

• MSK1 is a key mediator linking mitogenic and stress signals to CREB activation.
• The dual kinase domains and distinct activation pathways highlight MSK1's versatile role in cellular signaling.
• MSK1 represents a significant target for understanding and potentially modulating cellular responses to diverse stimuli.