Ben Cravatt

The promise and peril of chemical probes

Chemical probes are powerful reagents with increasing impacts on biomedical research. However, probes of poor quality or that are used incorrectly generate misleading results. To help address these shortcomings, we will create a community-driven wiki resource to improve quality and convey current best practice.

IGF1-R signals through the RON receptor to mediate pancreatic cancer cell migration

The RON receptor tyrosine kinase (RTK) is overexpressed in the majority of pancreatic cancers, yet its role in pancreatic cancer cell biology remains to be clarified. Recent work in childhood sarcoma identified RON as a mediator of resistance to insulin-like growth factor receptor (IGF1-R)-directed therapy. To better understand RON function in pancreatic cancer cells, we sought to identify novel RON interactants. Using multidimensional protein identification analysis, IGF-1R was identified and confirmed to interact with RON in pancreatic cancer cell lines. IGF-1 induces rapid phosphorylation of RON, but RON signaling did not activate IGF-1R indicating unidirectional signaling between these RTKs. We next demonstrate that IGF-1 induces pancreatic cancer cell migration that is RON dependent, as inhibition of RON signaling by either shRNA-mediated RON knockdown or by a RON kinase inhibitor abrogated IGF-1 induced wound closure in a scratch assay. In pancreatic cancer cells, unlike childhood sarcoma, STAT-3, rather than RPS6, is activated in response to IGF-1, in a RON-dependent manner. The current study defines a novel interaction between RON and IGF-1R and taken together, these two studies demonstrate that RON is an important mediator of IGF1-R signaling and that this finding is consistent in both human epithelial and mesenchymal cancers. These findings demand additional investigation to determine if IGF-1R independent RON activation is associated with resistance to IGF-1R-directed therapies in vivo and to identify suitable biomarkers of activated RON signaling.

Corrigendum: The promise and peril of chemical probes

Nat. Chem. Biol. 11, 536–541 (2015); published online 21 July 2015; corrected after print 16 September 2015. In the version of this Commentary initially published, there were several errors in the author list and author affiliations. Bryan Roth was incorrectly listed as “Brian Roth” and his correct affiliations are: The National Institute of Mental Health Psychoactive Active Drug Screening Program (NIMH PDSP), Department of Pharmacology, The University of North Carolina Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA and Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Glucagon and Thyroid Hormone: A Championship Team.

A bioactive peptide that combines glucagon with the thyroid hormone T3 lowers lipid levels, improves glucose tolerance, and promotes energy expenditure to treat symptoms and underlying causes of metabolic disease. The two active components both maximize their combined benefits and mitigate the negative consequences of treatment with each alone.

Erratum: Corrigendum: The promise and peril of chemical probes

Nat. Chem. Biol. 11, 536–541 (2015); published online 21 July 2015; corrected after print 16 September 2015. In the version of this Commentary initially published, there were several errors in the author list and author affiliations. Bryan Roth was incorrectly listed as “Brian Roth” and his correct affiliations are: The National Institute of Mental Health Psychoactive Active Drug Screening Program (NIMH PDSP), Department of Pharmacology, The University of North Carolina Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA and Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

Erratum: The promise and peril of chemical probes (Nature Chemical Biology (2015) 11 (536-541))

Nat. Chem. Biol. 11, 536–541 (2015); published online 21 July 2015; corrected after print 16 September 2015. In the version of this Commentary initially published, there were several errors in the author list and author affiliations. Bryan Roth was incorrectly listed as “Brian Roth” and his correct affiliations are: The National Institute of Mental Health Psychoactive Active Drug Screening Program (NIMH PDSP), Department of Pharmacology, The University of North Carolina Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA and Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.