1 research outputs found
Activating Mutations in <i>PIK3CA</i> Lead to Widespread Modulation of the Tyrosine Phosphoproteome
The
human oncogene <i>PIK3CA</i> is frequently mutated
in human cancers. Two hotspot mutations in <i>PIK3CA</i>, E545K and H1047R, have been shown to regulate widespread signaling
events downstream of AKT, leading to increased cell proliferation,
growth, survival, and motility. We used quantitative mass spectrometry
to profile the global phosphotyrosine proteome of isogenic knock-in
cell lines containing these activating mutations, where we identified
824 unique phosphopeptides. Although it is well understood that these
mutations result in hyperactivation of the serine/threonine kinase
AKT, we found a surprisingly widespread modulation of tyrosine phosphorylation
levels of proteins in the mutant cells. In the tyrosine kinome alone,
29 tyrosine kinases were altered in their phosphorylation status.
Many of the regulated phosphosites that we identified were located
in the kinase domain or the canonical activation sites, indicating
that these kinases and their downstream signaling pathways were activated.
Our study demonstrates that there is frequent and unexpected cross-talk
that occurs between tyrosine signaling pathways and serine/threonine
signaling pathways activated by the canonical PI3K-AKT axis