Signal transducer and activator of transcription 3 and the phosphatidylinositol 3‐kinase regulatory subunits p55α and p50α regulate autophagy <i>in vivo</i>

Pensa, Sara; Lloyd-Lewis, Bethan; Sargeant, Timothy J.; Resemann, Henrike K; Kahn, C. Ronald; Watson, Christine J.

doi:10.1111/febs.13035

Cited by 23 publications

(24 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus STAT3-mediated upregulation of CTSB and CTSL enhances cell death by lysosomal membrane permeabilization (LMP) during mammary gland involution, 45 whereas LMP impairs autophagy because the autophagy flux requires functional lysosomes. 46 As described above, nuclear STAT3 executes anti-autophagic functions by upregulating negative regulators of autophagy such as BCL2, BCL2L1, MCL1, PIK3R1/p55a, and PIK3R1/p50a, or by downregulating essential autophagy genes such as BECN1 and PIK3C3. However, STAT3 also executes its pro-autophagic function by modulating the hypoxic expression of HIF1A (hypoxia inducible factor 1, a subunit [basic helix-loop-helix transcription factor]) and BNIP3.…”

Section: Stat3 In Autophagymentioning

confidence: 98%

“…STAT3 suppresses autophagy in mammary gland cells by directly upregulating the PIK3R1/ p55a and PIK3R1/p50a (phosphoinositide-3-kinase, regulatory subunit 1 [a], p55a and p50a isoforms), which function as inhibitors of PIK3R1/p85a-mediated autophagy. 46 In addition, STAT3 transcriptionally enhances the expression of CTSB (cathepsin B) and CTSL (cathepsin L), possibly through the downregulation of Serpina3g, a known target of NFKB1 in memory T cells. 45 STAT3 can inhibit the transcriptional activity of NFKB1 by binding to NFKB1 and RELA, subsequently downregulating its target genes, including Serpina3g.…”

Section: Stat3 In Autophagymentioning

confidence: 99%

See 1 more Smart Citation

The role of STAT3 in autophagy

et al. 2015

View full text Add to dashboard Cite

Abbreviations: ALK, anaplastic lymphoma receptor tyrosine kinase; ATF4, activating transcription factor 4; BNIP3, BCL2/adenovirus E1B 19kDa interacting protein 3; CNTF, ciliary neurotrophic factor; COX8, cytochrome c oxidase subunit VIII; ConA, concanavalin A; CTSB, cathepsin B; CTSL, cathepsin L; CuB, cucurbitacin B; CYCS, cytochrome c, somatic; EGF, epidermal growth factor; EIF2A, eukaryotic initiation factor 2A, 65kDa; EIF2AK2, eukaryotic translation initiation factor 2-a kinase 2; ER, endoplasmic reticulum; ETC, electron transport chain; FOXO1/3, forkhead box O1/3; HDAC3, histone deacetylase 3; HIF1A, hypoxia inducible factor 1, a subunit (basic helix-loop-helix transcription factor); IL6, interleukin 6; IMM, inner mitochondrial membrane; KDR, kinase insert domain receptor; LMP, lysosomal membrane permeabilization; MAPK1, mitogen-activated protein kinase 1; MAP1LC3A, microtubule-associated protein 1 light chain 3 a; miRNA, microRNA; mitoSTAT3, mitochondrial STAT3; MLS, mitochondrial localization sequence; MMP14, matrix metallopeptidase 14 (membrane-inserted); NDUFA13, NADH dehydrogenase (ubiquinone) 1 a subcomplex, 13; NES, nuclear export signal; NFKB1, nuclear factor of kappa light polypeptide gene enhancer in B-cells 1; NLS, nuclear localization signal; PDGFRB, platelet-derived growth factor receptor, b polypeptide; PRKAA2, protein kinase, AMP-activated, a 2 catalytic subunit; PTPN2, protein tyrosine phosphatase, non-receptor type 2; PTPN6, protein tyrosine phosphatase, non-receptor type 6; PTPN11, protein tyrosine phosphatase, non-receptor type 11; ROS, reactive oxygen species; RTK, receptor tyrosine kinases; SH2, src homology 2; STAT3, signal transducer and activator of transcription 3 (acute-phase response factor); VHL, von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase; XPO1, exportin 1.Autophagy is an evolutionarily conserved process in eukaryotes that eliminates harmful components and maintains cellular homeostasis in response to a series of extracellular insults. However, these insults may trigger the downstream signaling of another prominent stress responsive pathway, the STAT3 signaling pathway, which has been implicated in multiple aspects of the autophagic process. Recent reports further indicate that different subcellular localization patterns of STAT3 affect autophagy in various ways. For example, nuclear STAT3 fine-tunes autophagy via the transcriptional regulation of several autophagy-related genes such as BCL2 family members, BECN1, PIK3C3, CTSB, CTSL, PIK3R1, HIF1A, BNIP3, and microRNAs with targets of autophagy modulators. Cytoplasmic STAT3 constitutively inhibits autophagy by sequestering EIF2AK2 as well as by interacting with other autophagy-related signaling molecules such as FOXO1 and FOXO3. Additionally, the mitochondrial translocation of STAT3 suppresses autophagy induced by oxidative stress and may effectively preserve mitochondria from being degraded by mitophagy. Understanding the role of STAT3 signaling in the regulation of autophagy may provide insight into the cla...

show abstract

Section: Stat3 In Autophagymentioning

confidence: 98%

Section: Stat3 In Autophagymentioning

confidence: 99%

The role of STAT3 in autophagy

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Nuclear STAT3 executes antiautophagic functions by upregulating negative regulators of autophagy such as BCL2, BCL2L1, MCL1, PIK3R1/p55 α and PIK3R1/p50 α . 76, 77, 78 Furthermore, STAT3 disrupts the formation of the pro-autophagic BCN1/PI3K-III complex by recruiting histone deacetylase 3 (HDAC3) to the promoter of BECN1 and repressing its expression. During EMT Integrin profiles and Integrin-ECM contacts undergo profound reorganization (Figure 4).…”

Section: Shared Signaling Pathways and Molecular Mediatorsmentioning

confidence: 99%

Autophagy and epithelial–mesenchymal transition: an intricate interplay in cancer

Gugnoni¹,

Sancisi²,

Manzotti³

et al. 2016

Cell Death Dis

165

150

View full text Add to dashboard Cite

Autophagy and epithelial to mesenchymal transition (EMT) are major biological processes in cancer. Autophagy is a catabolic pathway that aids cancer cells to overcome intracellular or environmental stress, including nutrient deprivation, hypoxia and drugs effect. EMT is a complex transdifferentiation through which cancer cells acquire mesenchymal features, including motility and metastatic potential. Recent observations indicate that these two processes are linked in a complex relationship. On the one side, cells that underwent EMT require autophagy activation to survive during the metastatic spreading. On the other side, autophagy, acting as oncosuppressive signal, tends to inhibit the early phases of metastasization, contrasting the activation of the EMT mainly by selectively destabilizing crucial mediators of this process. Currently, still limited information is available regarding the molecular hubs at the interplay between autophagy and EMT. However, a growing number of evidence points to the functional interaction between cytoskeleton and mitochondria as one of the crucial regulatory center at the crossroad between these two biological processes. Cytoskeleton and mitochondria are linked in a tight functional relationship. Controlling mitochondria dynamics, the cytoskeleton cooperates to dictate mitochondria availability for the cell. Vice versa, the number and structure of mitochondria, which are primarily affected by autophagy-related processes, define the energy supply that cancer cells use to reorganize the cytoskeleton and to sustain cell movement during EMT. In this review, we aim to revise the evidence on the functional crosstalk between autophagy and EMT in cancer and to summarize the data supporting a parallel regulation of these two processes through shared signaling pathways. Furthermore, we intend to highlight the relevance of cytoskeleton and mitochondria in mediating the interaction between autophagy and EMT in cancer.

show abstract

“…In the absence of active STAT5, a loss-of-function of STAT3 or its upstream regulator JAK1 significantly extends the functional competence of secretory epithelial cells and causes a delay in cell death and mammary gland remodeling (Chapman et al, 1999; Sakamoto et al, 2016b). The activation of STAT3 enhances the expression of p50α/p55α, and the analysis of an isoform specific knockout mouse model revealed that these smaller PI3 kinase regulatory subunits are involved in the programmed death of mammary epithelial cells (Figure 1), possibly through upregulation of cathepsin L (Pensa et al, 2014b) or though inhibition of autophagy (Pensa et al, 2014a). The model previously proposed by Abell et al (2005) that p50α and p55α inhibit the p85α/p110α PI3K holoenzyme and AKT1 needs to be revisited since the loss of active STAT5 during the onset of involution causes a swift decline in p85α, p110α, and AKT1 expression.…”

Section: Jak2/stat5 Signaling Promotes the Survival Of Mammary Epithementioning

confidence: 99%

Crosstalk between STAT5 activation and PI3K/AKT functions in normal and transformed mammary epithelial cells

Rädler

Wehde

Wagner

2017

Molecular and Cellular Endocrinology

View full text Add to dashboard Cite

Summary Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) have been shown to function downstream of several peptide hormones and cytokines that are required for postnatal development and secretory function of the mammary gland. As part of an extended network, these signal transducers can engage in crosstalk with other pathways to facilitate synergistic, and sometimes antagonistic, actions of different growth factors. Specifically, signaling through the JAK2/STAT5 cascade has been demonstrated to be indispensable for the specification, proliferation, differentiation, and survival of secretory mammary epithelial cells. Following a concise description of major cellular programs in mammary gland development and the role of growth factors that rely on JAK/STAT signaling to orchestrate these programs, this review highlights the significance of active STAT5 and its crosstalk with the PI3 kinase and AKT1 for mediating the proliferation of alveolar progenitors and survival of their functionally differentiated descendants in the mammary gland. Based on its ability to provide self-sufficiency in growth signals that are also capable of overriding intrinsic cell death programs, persistently active STAT5 can serve as a potent oncoprotein that contributes to the genesis of breast cancer. Recent experimental evidence demonstrated that, similar to normal developmental programs, oncogenic functions of STAT5 rely on molecular crosstalk with PI3K/AKT signaling for the initiation, and in some instances the progression, of breast cancer. The multitude by which STATs can interact with individual mediators of the PI3K/AKT signaling cascade may provide novel avenues for targeting signaling nodes within molecular networks that are crucial for the survival of cancer cells.

show abstract

Signal transducer and activator of transcription 3 and the phosphatidylinositol 3‐kinase regulatory subunits p55α and p50α regulate autophagy in vivo

Cited by 23 publications

References 27 publications

The role of STAT3 in autophagy

The role of STAT3 in autophagy

Autophagy and epithelial–mesenchymal transition: an intricate interplay in cancer

Crosstalk between STAT5 activation and PI3K/AKT functions in normal and transformed mammary epithelial cells

Contact Info

Product

Resources

About