Stress-activated kinases regulate protein stability

The key question is what events target speci®c proteins for ubiquitination at one time and prevent ubiquitination at other times? In this review, we develop the notion that there is a direct relationship between the phosphorylation/dephosphorylation cascade of the signal transduction pathways and the targeting of the regulatory proteins for ubiquitination

Serge Y Fuchs; Victor A Fried; Ze'ev Ronai


Scholarcy highlights

  • The ubiquitin-proteasome pathway has been implicated in the degradation of a variety of di€erent proteins in vitro, but it was not until the availability of speci®c proteasome inhibitors that could be used in living cells did it become apparent that this system was responsible for the degradation of speci®c proteins as part of normal cellular regulatory pathways
  • The proteolysis process is not always constitutive and can be regulated by a variety of extra- and intracellular signals, targeting proteins for Correspondence: Z Ronai ubiquitination is a dynamic process that is necessary for regulating protein stability
  • The emerging model from these observations suggests that Jun NH2kinase, by virtue of its targeting for ubiquitination, is the key regulator of its associated proteins, c-jun, ATF2 and JunB in non-stressed normal growing cells
  • Stimulation by interleukin 3 in the presence of proteasome inhibitors led to stable phosphorylation and prolonged activation of JAK2 and JAK1 suggesting that proteasome-mediated protein degradation can modulate the activity of the Janus kinase/signal transducers and activators of transcription pathway by regulating the deactivation of JAK
  • The c-mos proto-oncogene product is a serine/threonine kinase that is directly phosphorylated by the mitogen-activated protein kinase/ ERK kinase and, as a result, activates mitogenactivated protein kinases in response to a variety of mitogenic signals in the germline cells
  • The regulation of protein targeting for ubiquitination dictates the duration and magnitude of a protein's ability to perform its cellular function; our current understanding provides new opportunities for insight into key cellular regulatory processes in normal growing, stressed, and transformed cells

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