Cell-to-Cell Variability in PI3K Protein Level Regulates PI3K-AKT Pathway Activity in Cell Populations

Yuan, Tina L.; Wulf, Gerburg M.; Burga, Laura N.; Cantley, Lewis C.

doi:10.1016/j.cub.2010.12.047

Cited by 92 publications

(94 citation statements)

References 39 publications

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“…We detected increased PI3K signaling in each of the PI3K-H1047R mutant engineered cell lines grown in spheroid culture, as assessed by Western blot analysis of serine 473 of the downstream effector protein AKT ( Fig. 2A and B), similar to previous reports (20,(29)(30)(31)(32)(33). In addition, we observed an increase in phosphorylated S6 ribosomal protein, which lies downstream of AKT (Supplementary Fig.…”

Section: Pi3k Wt and Mutant Engineered Cells Exhibit A Range Of Resposupporting

confidence: 75%

Heregulin–ErbB3-Driven Tumor Growth Persists in PI3 Kinase Mutant Cancer Cells

Yarar

Lahdenranta

Kubasek

et al. 2015

Molecular Cancer Therapeutics

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PI3K is frequently mutated in cancer and plays an important role in cell growth and survival. Heregulin (HRG)-mediated autocrine or paracrine signaling through the receptor tyrosine kinase ErbB3 potently activates the PI3K/AKT pathway and has been shown to mediate resistance to a wide variety of anticancer agents. Although PI3K functions downstream of HRG-ErbB3, it is unknown whether activating mutations in PI3K render HRG ineffective. If so, patients with PI3K mutations would not be expected to benefit from ErbB3-directed therapies. Here, we find that a subset of cell lines harboring activating PI3K mutations can be further growth-stimulated by HRG, and this effect is blocked by incubation with seribantumab (MM-121), a monoclonal antiErbB3 antibody. Although expression of mutant PI3K in wild-type PI3K cells frequently results in loss of HRG-stimulated growth, some cell lines continue to respond to HRG. In cell lines where HRG-stimulated growth is lost, this loss is invariably accompanied by a reduction in ErbB3 levels, a corresponding increase in basal phosphorylation levels of FOXO-family transcription factors, and a reduction in HRG-induced downstream signaling. Importantly, HRG-stimulated growth is partially rescued by reexpressing ErbB3. This response is blocked by seribantumab, indicating that ErbB3 levels rather than downstream signaling proteins limit HRG-stimulated growth in PI3K mutant cells.

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Section: Pi3k Wt and Mutant Engineered Cells Exhibit A Range Of Resposupporting

confidence: 75%

Heregulin–ErbB3-Driven Tumor Growth Persists in PI3 Kinase Mutant Cancer Cells

Yarar

Lahdenranta

Kubasek

et al. 2015

Molecular Cancer Therapeutics

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“…Chen et al (2005) have shown that, in mouse models of prostate cancer, loss of PTEN drives cells into senescence. Yuan et al (2011) have shown data indicating that high levels of PI-3-kinase activity can drive breast epithelial cells into senescence. These differences may be a reflection of the striking tissuespecific effects of relatively small changes in signaling through the PI-3-kinase pathway (Carracedo et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Repression of cancer cell senescence by PKCι

et al. 2011

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“…In addition, recent work shows that dephosphorylation of the p110-free p85␤ regulatory subunit leads to its degradation through F-box protein FBXL2 (12). Importantly, the catalytic subunit PIK3CA may also be subject to a similar regulation: that is, a dynamic cycle of proteasomedependent degradation and resynthesis of PIK3CA was observed in response to the stimulation of epidermal growth factor (13).…”

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confidence: 99%

NEDD4L Protein Catalyzes Ubiquitination of PIK3CA Protein and Regulates PI3K-AKT Signaling

Wang

Dang

Liu

et al. 2016

Journal of Biological Chemistry

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Oncogenic PIK3CA (p110␣), the catalytic subunit of class IA PI3K, plays a major role in PI3K-related cancer progression. The mechanisms underlying the dynamic regulation of PIK3CA protein levels remain unknown. Here we demonstrated that PIK3CA is regulated by polyubiquitination. We identified NEDD4L as the E3 ligase that catalyzes PIK3CA polyubiquitination, leading to its proteasome-dependent degradation. NEDD4L ubiquitinates both the free and regulatory subunitbound PIK3CA but does not ubiquitinate the regulatory subunit of PI3K. Overexpression of NEDD4L accelerates the turnover rate of PIK3CA, whereas suppression of NEDD4L results in not only the accumulation of PIK3CA but also a paradoxical decrease of AKT activation. Thus, we propose that NEDD4L negatively regulates PIK3CA protein levels via ubiquitination and is required for the maintenance of PI3K-AKT signaling pathway.Class IA phosphoinositide 3-kinases (PI3Ks) are lipid kinases that integrate signals from growth factors and hormones to regulate multiple cellular process including growth, proliferation, migration, and survival (1). In response to activation of various growth factor receptors, PI3K is recruited to the cell membrane to catalyze the production of phosphoinositide-3,4,5-trisphosphate, a second messenger required for the activation of a series of downstream kinases (1, 2). Class IA PI3K is composed of a catalytic subunit (p110) and a regulatory subunit (p85), which are demonstrated to form an obligatory heterodimer (3). PIK3CA (p110␣), a major isoform of the catalytic subunits, is widely expressed in various tissues (4). Somatic mutations in PIK3CA occur frequently in cancers of the breast, colon, endometrium, and prostate as well as glioblastomas (5-7). Gain of PIK3CA copy number leads to increased PIK3CA protein levels and is also associated with human cancers (4,8,9). These observations indicate that dysregulation of PI3K plays an important role in cancer emergence and development, underscoring the significance of understanding the regulation mechanisms of PI3K signaling pathway.PI3K function can be modulated via its gene expression or its association with Ras, receptor-tyrosine kinases and other adaptor proteins such as insulin receptor substrate1/2 (IRS1/2). It can also be regulated through post-translational modifications. For instance, previous reports demonstrate that the p85 regulatory subunit can be polyubiquitinated and negatively regulated by the E3 ubiquitin ligase Cbl-b in T cells without affecting its protein level (10, 11). In addition, recent work shows that dephosphorylation of the p110-free p85␤ regulatory subunit leads to its degradation through F-box protein FBXL2 (12). Importantly, the catalytic subunit PIK3CA may also be subject to a similar regulation: that is, a dynamic cycle of proteasomedependent degradation and resynthesis of PIK3CA was observed in response to the stimulation of epidermal growth factor (13).To further understand the regulation of PIK3CA, we developed an in vitro ubiquitination assay for PIK3CA. Usin...

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Cell-to-Cell Variability in PI3K Protein Level Regulates PI3K-AKT Pathway Activity in Cell Populations

Cited by 92 publications

References 39 publications

Heregulin–ErbB3-Driven Tumor Growth Persists in PI3 Kinase Mutant Cancer Cells

Heregulin–ErbB3-Driven Tumor Growth Persists in PI3 Kinase Mutant Cancer Cells

Repression of cancer cell senescence by PKCι

NEDD4L Protein Catalyzes Ubiquitination of PIK3CA Protein and Regulates PI3K-AKT Signaling

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