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Same protein that fires up cancer-promoting Erk also blocks its activation
Date:4/19/2013

ool and of finding small molecule drugs that block growth-factor signaling to Shc, keeping it bound to Erk, Ladbury noted.

Growth factors provide double boost for Erk

When the appropriate growth factor receptor is stimulated Erk is activated in the MAP Kinase pathway. It dives into the cell nucleus and turns on a variety of genes, actions that contribute to cancer proliferation, blood vessel production and metastasis when signaling is out of control.

When receptor tyrosine kinases on the cell surface connect with growth factors, they normally send a signal via Shc that sets off a chain of actions leading to Erk activation. Ladbury and colleagues looked at Shc's connections to epidermal growth factor receptor (EGFR) signaling.

The team found in mammalian cell lines that:

  • Under non-stimulated conditions Shc binds to Erk in the cell cytoplasm at binding sites that are unique on both proteins.
  • Stimulation via EGFR reduces this connection, but not by competing with Shc at the Shc-Erk binding site.
  • Instead, on stimulation from outside the cells, EGFR adds phosphate groups to itself at specific sites. One of these forms a binding for Shc, which distorts the protein's shape, making it impossible for Erk to bind.
  • Overexpression of Shc decreases the amount of activated Erk, because Shc mops up free Erk molecules.
  • Depleting Shc expression with short hairpin RNA resulted in higher levels of activated Erk.
  • When separated from Shc, Erk moves into the nucleus and activates genes even when the cell is not receiving a stimulus. Thus without the controlling influence of Shc, Erk can run riot in the cell giving rise to unrestrained cell reproduction.

Shc-Erk connection confirmed

Ladbury and colleagues then tested their results in the C.Elegans, a worm model frequently employed in biological research. Both Shc and Erk are greatly similar between humans and the worms.

Experime
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Contact: Scott Merville
smerville@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert

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