p55PIK-PI3K stimulates angiogenesis in colorectal cancer cell by activating NF-κB pathway

Wang, Guihua; Chen, Cheng; Yang, Rui; Cao, Xiaoyan; Lai, Senyan; Luo, Xuelai; Feng, Yongdong; Xia, Xianmin; Gong, Jianping; Hu, Junbo

doi:10.1007/s10456-013-9336-y

Cited by 33 publications

(30 citation statements)

References 48 publications

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“…Thus, we propose that BMP2-induced PI3K signalling is transduced specifically by the p55γ/p110α class Ia PI3K complex. This could be of particular importance for cancer therapy because activating mutations in p110α are frequently found in human cancers, and p55γ is differentially up-regulated in several tumours, which is sufficient to stimulate tumour angiogenesis [45]. This, together with the crucial role of BMP2 in oncogenic transformation and tumour angiogenesis [46-48], suggests that the p55γ/p110α complex positively regulates BMP2-induced motility, chemotaxis, and invasion of endothelial and cancer cells [9,49,50].…”

Section: Discussionmentioning

confidence: 99%

BMP2-induced chemotaxis requires PI3K p55γ/p110α-dependent phosphatidylinositol (3,4,5)-triphosphate production and LL5β recruitment at the cytocortex

et al. 2014

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BackgroundBMP-induced chemotaxis of mesenchymal progenitors is fundamental for vertebrate development, disease and tissue repair. BMP2 induces Smad and non-Smad signalling. Whereas signal transduction via Smads lead to transcriptional responses, non-Smad signalling induces both, transcriptional and immediate/early non-transcriptional responses. However, the molecular mechanisms by which BMP2 facilitates planar cell polarity, cortical actin rearrangements, lamellipodia formation and chemotaxis of mesenchymal progenitors are poorly understood. Our aim was to uncover the molecular mechanism by which BMP2 facilitates chemotaxis via the BMP2-dependent activation of PI3K and spatiotemporal control of PIP3 production important for actin rearrangements at the mesenchymal cell cytocortex.ResultsWe unveiled the molecular mechanism by which BMP2 induces non-Smad signalling by PI3K and the role of the second messenger PIP3 in BMP2-induced planar cell polarity, cortical actin reorganisation and lamellipodia formation. By using protein interaction studies, we identified the class Ia PI3K regulatory subunit p55γ to act as a specific and non-redundant binding partner for BMP receptor type II (BMPRII) in concert with the catalytic subunit p110α. We mapped the PI3K interaction to a region within the BMPRII kinase. Either BMP2 stimulation or increasing amounts of BMPRI facilitated p55γ association with BMPRII, but BMPRII kinase activity was not required for the interaction. We visualised BMP2-dependent PIP3 production via PI3K p55γ/p110α and were able to localise PIP3 to the leading edge of intact cells during the process of BMP2-induced planar cell polarity and actin dependent lamellipodia formation. Using mass spectrometry, we found the highly PIP3-sensitive PH-domain protein LL5β to act as a novel BMP2 effector in orchestrating cortical actin rearrangements. By use of live cell imaging we found that knock-down of p55γ or LL5β or pharmacological inhibition of PI3K impaired BMP2-induced migratory responses.ConclusionsOur results provide evidence for an important contribution of the BMP2-PI3K (p55γ/p110α)- PIP3-LL5β signalling axis in mesenchymal progenitor cell chemotaxis. We demonstrate molecular insights into BMP2-induced PI3K signalling on the level of actin reorganisation at the leading edge cytocortex. These findings are important to better understand BMP2–induced cytoskeletal reorganisation and chemotaxis of mesenchymal progenitors in different physiological or pathophysiological contexts.

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Section: Discussionmentioning

confidence: 99%

BMP2-induced chemotaxis requires PI3K p55γ/p110α-dependent phosphatidylinositol (3,4,5)-triphosphate production and LL5β recruitment at the cytocortex

et al. 2014

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“…Several studies have reported that PIK3R3 is abnormally overexpressed in some types of cancer, such as lung cancer, colorectal cancer, and gastric cancer [14-16]. Data obtained from clinical samples suggested that overexpression of this molecule is significantly associated with the progression and prognosis of certain cancers, and functional assays demonstrated that PIK3R3 could promote the proliferation, migration, and invasion of some cancers in vitro and vivo [17-19]. Some studies have mentioned the role of PIK3R3 in PC [20, 21].…”

Section: Introductionmentioning

confidence: 99%

PIK3R3 Promotes Metastasis of Pancreatic Cancer via ZEB1 Induced Epithelial-Mesenchymal Transition

Peng

Zhu

Yin

et al. 2018

Cell Physiol Biochem

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Background/Aims: PIK3R3 is a regulatory subunit of phosphatidylinositol 3-kinase (PI3K) which plays an essential role in the metastasis of several types of cancer. However, whether PIK3R3 can promote the metastasis of pancreatic cancer (PC) is still unclear. In this study, we characterized the role of PIK3R3 in metastasis of PC and underlying potential mechanisms. Methods: RT-PCR, western blot, immunofluorescence (IF) and immunohistochemistry (IHC) were applied to investigate the expression of genes and proteins in different cell lines and tissues. To assess the function of PIK3R3 and related mechanisms, the cells with RNAi-mediated knockdown or overexpression were used to perform a series of in vitro and in vivo assays. Results: PIK3R3 was significantly overexpressed in pancreatic cancer tissues, especially in metastatic cancer tissues, as well as in pancreatic cancer cells. Functional assays suggested that overexpression or knockdown of PIK3R3 could respectively promote or suppress the migration and invasion of PC cells in vitro and in vivo. Further mechanism related studies demonstrated that ERK1/2-ZEB1 pathway-triggered epithelial-mesenchymal transition (EMT) might be responsible for the PIK3R3-induced PC cell migration and invasion. Conclusion: PIK3R3 could promote the metastasis of PC by facilitating ZEB1 induced EMT, and could act as a potential therapeutic target to limit PC metastasis.

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“…In the previous reports, p55g regulatory subunit of PI3K promoted cell cycle progression 56 , DNA synthesis 57 , proliferation and differentiation of leukemia cells 58 , and tumour angiogenesis via regulation of NF-kB signalling or expression of VEGF-A 59 . Furthermore, the protein levels of p55g increased in colorectal, gastric and ovarian cancers 56,59,60 . PI3K also plays an important role in the multiple steps of neurite outgrowth during nerve growth factorstimulated differentiation and in the brain development 61 .…”

Section: Discussionmentioning

confidence: 99%

RNAi-based functional selection identifies novel cell migration determinants dependent on PI3K and AKT pathways

et al. 2014

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Lentiviral short hairpin RNA (shRNA)-mediated genetic screening is a powerful tool for identifying loss-of-function phenotype in mammalian cells. Here, we report the identification of 91 cell migration-regulating genes using unbiased genome-wide functional genetic selection. Individual knockdown or cDNA overexpression of a set of 10 candidates reveals that most of these cell migration determinants are strongly dependent on the PI3K/PTEN/ AKT pathway and on their downstream signals, such as FOXO1 and p70S6K1. ALK, one of the cell migration promoting genes, uniquely uses p55g regulatory subunit of PI3K, rather than more common p85 subunit, to trigger the activation of the PI3K-AKT pathway. Our method enables the rapid and cost-effective genome-wide selection of cell migration regulators. Our results emphasize the importance of the PI3K/PTEN/AKT pathway as a point of convergence for multiple regulators of cell migration.

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p55PIK-PI3K stimulates angiogenesis in colorectal cancer cell by activating NF-κB pathway

Cited by 33 publications

References 48 publications

BMP2-induced chemotaxis requires PI3K p55γ/p110α-dependent phosphatidylinositol (3,4,5)-triphosphate production and LL5β recruitment at the cytocortex

BMP2-induced chemotaxis requires PI3K p55γ/p110α-dependent phosphatidylinositol (3,4,5)-triphosphate production and LL5β recruitment at the cytocortex

PIK3R3 Promotes Metastasis of Pancreatic Cancer via ZEB1 Induced Epithelial-Mesenchymal Transition

RNAi-based functional selection identifies novel cell migration determinants dependent on PI3K and AKT pathways

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