Research Article: A Predictive Phosphorylation Signature of Lung Cancer

Date Published: November 25, 2009

Publisher: Public Library of Science

Author(s): Chang-Jiun Wu, Tianxi Cai, Klarisa Rikova, David Merberg, Simon Kasif, Martin Steffen, Chad Creighton.

Abstract: Aberrant activation of signaling pathways drives many of the fundamental biological processes that accompany tumor initiation and progression. Inappropriate phosphorylation of intermediates in these signaling pathways are a frequently observed molecular lesion that accompanies the undesirable activation or repression of pro- and anti-oncogenic pathways. Therefore, methods which directly query signaling pathway activation via phosphorylation assays in individual cancer biopsies are expected to provide important insights into the molecular “logic” that distinguishes cancer and normal tissue on one hand, and enables personalized intervention strategies on the other.

Partial Text: At the molecular level, cancers are heterogeneous diseases, arising from genetic factors, environmental carcinogens and random, somatic mutation [1]. Phosphorylation of proteins is a key regulator of protein activity [2], and in particular, modification of tyrosine residues modulate critical signaling and control processes [3]. In cancers, aberrant phosphorylation status of key residues (its presence or absence) has been observed and documented in many studies, which include the original oncogene, src [4], and many others [5].

The results presented in this paper open the door to a number of future directions in both basic and translational research. Understanding the precise role of phosphorylation measurement in regulation of signaling pathways in cancer remains an important challenge, and we primarily focused on the role of EGFR and cell proliferation pathways. We have identified a set of tyrosine residues that are differentially phosphorylated in cancerous and normal lung tissue. More than mRNA transcript or protein expression levels, the phosphorylation status of select residues are related to the functional activity of the associated gene products. This is potentially particularly important in cancers as the presence or absence of various receptor proteins may not reflect the activity of downstream signaling intermediates. This scenario could be important in at least two cases with respect to signaling pathways, one in which a receptor is present, but there is no activating ligand (or an abundance of a non-functioning ligand) to initiate downstream signaling events, or if the receptor is present, but mutated and inactive and therefore unable to transmit the binding signal.



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