Salt‐inducible kinase 1 regulates E‐cadherin expression and intercellular junction stability

Eneling, Kristina; Brion, Laura; Pinto, Vanda; Pinho, Maria João; Sznajder, Jacob I.; Mochizuki, Naoki; Emoto, Kazuo; Soares-da-Silva, Patrı́cio; Bertorello, Alejandro M.

doi:10.1096/fj.12-205609

Cited by 30 publications

(38 citation statements)

References 40 publications

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“…IPMK, an upstream kinase in the inositol polyphosphate synthesis pathway, influences LKB1 activity in a catalytic activity-dependent manner (32), suggesting that higher inositol phosphates regulate LKB1. LKB1 has been reported to suppress FAK activity-dependent migration/invasion and metastasis (16,33,34), as well as to enhance E-cadherin levels (17,19). Using MCF7 and H1299 cells with LKB1 depletion, we confirm that LKB1 down-regulates cell spreading (Fig.…”

Section: Significancesupporting

confidence: 67%

“…Recent evidence suggests that the antimetastatic actions of LKB1 could stem from AMPK-independent down-regulation of the cell-matrix focal adhesion process (16,33,34) or up-regulation of E-cadherin-based cell-cell adhesive properties (17,19). Here we show that these two opposing processes can be simultaneously altered by LKB1 knockdown, suggesting that LKB1 controls the balance between cell-cell and cell-matrix adhesion.…”

Section: Discussionsupporting

confidence: 49%

“…Cell-cell adhesion and cell migration/invasion are primarily driven by E-cadherinmediated cell clustering (14) and focal-adhesion-based cellmatrix interactions (15), respectively. Whether these two distinct adhesion processes are concurrently or independently regulated remains poorly understood.The tumor suppressor LKB1 has been separately reported to inhibit FAK activation (16) and to enhance E-cadherin expression (17)(18)(19). LKB1 is mutated in Peutz-Jeghers syndrome patients who tend to develop cancer at multiple sites (20).…”

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confidence: 99%

“…The tumor suppressor LKB1 has been separately reported to inhibit FAK activation (16) and to enhance E-cadherin expression (17)(18)(19). LKB1 is mutated in Peutz-Jeghers syndrome patients who tend to develop cancer at multiple sites (20).…”

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confidence: 99%

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Inositol pyrophosphates promote tumor growth and metastasis by antagonizing liver kinase B1

Rao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The inositol pyrophosphates, molecular messengers containing an energetic pyrophosphate bond, impact a wide range of biologic processes. They are generated primarily by a family of three inositol hexakisphosphate kinases (IP6Ks), the principal product of which is diphosphoinositol pentakisphosphate (IP7). We report that IP6K2, via IP7 synthesis, is a major mediator of cancer cell migration and tumor metastasis in cell culture and in intact mice. IP6K2 acts by enhancing cell-matrix adhesion and decreasing cell-cell adhesion. This action is mediated by IP7-elicited nuclear sequestration and inactivation of the tumor suppressor liver kinase B1 (LKB1). Accordingly, inhibitors of IP6K2 offer promise in cancer therapy.I nositol pyrophosphates, conserved eukaryotic messenger molecules with a pyrophosphate bond, mediate numerous physiologic processes including regulation of Akt (1), insulin secretion (2), ATP production (3), DNA repair (4), and damage response (5). Exemplified by diphosphoinositol pentakisphosphate (PPIP5, IP7), inositol pyrophosphates are primarily generated by a family of three inositol hexakisphosphate (IP6) kinases (IP6K) (6, 7) and also may be formed by a more recently described group of IP6/7 kinases (8). IP6K1 and IP6K2 are widely distributed, whereas IP6K3 is expressed primarily in the brain (9). A related enzyme, inositol polyphosphate multikinase (IPMK), converts IP3 to IP4 and IP5, displays physiologic PI3 kinase activity (10), and noncatalytically acts as a transcriptional coactivator (11) and stabilizer of the mTOR complex-1 (12). Whether IP6Ks and IPMK play direct roles in tumor progression remains unexplored.Tumor cell metastasis requires loss of cell-cell adhesion and gain of migratory and invasive properties, a collective program known as epithelial-mesenchymal transition (EMT), which is also critical for embryonic development (13). Cell-cell adhesion and cell migration/invasion are primarily driven by E-cadherinmediated cell clustering (14) and focal-adhesion-based cellmatrix interactions (15), respectively. Whether these two distinct adhesion processes are concurrently or independently regulated remains poorly understood.The tumor suppressor LKB1 has been separately reported to inhibit FAK activation (16) and to enhance E-cadherin expression (17)(18)(19). LKB1 is mutated in Peutz-Jeghers syndrome patients who tend to develop cancer at multiple sites (20). As a master kinase controlling the activity of AMPK and 13 other AMPK-like kinases (21), LKB1 mediates diverse cellular processes such as polarity, adhesion, metabolism, tumor growth/metastasis, and neuronal axon initiation/branching (22). Unlike conventional protein kinases, LKB1 is not activated by activation loop phosphorylation but by protein-protein interaction with two other subunits of the heterotrimeric holoenzyme: STRAD and Mo25. LKB1 can also exist as an inactive nuclear monomer. STRAD binds and stabilizes LKB1 (23) in the cytosol, where it is phosphorylated at serine 428 by PKCζ (24). Whether cytosolic localization enhance...

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Section: Significancesupporting

confidence: 67%

Section: Discussionsupporting

confidence: 49%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Inositol pyrophosphates promote tumor growth and metastasis by antagonizing liver kinase B1

Rao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…3 In addition, SIK1 regulates active sodium transport in renal and lung epithelia by increasing sodium-potassium ATPase (Na + ,K + -ATPase) activity and mediates gene expression activation in cardiac myocytes on increase in intracellular sodium. [4][5][6] SIK1 is also present in the vasculature and its activity in endothelial and vascular smooth muscle cells (VSMCs) seems to be relevant for controlling the vascular tone and arterial blood pressure by regulating Na + ,K + -ATPase activity in VSMCs. 7 A polymorphism in SIK1 gene resulting in 1 amino acid change ( 15 Gly→Ser) in the protein enhances the kinase activity and is associated with lower blood pressure and reduced left ventricle (LV) mass index in humans.…”

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confidence: 99%

Increased Arterial Blood Pressure and Vascular Remodeling in Mice Lacking Salt-Inducible Kinase 1 (SIK1)

Bertorello

Pires

Igreja

et al. 2015

Circulation Research

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Rationale:In human genetic studies a single nucleotide polymorphism within the salt-inducible kinase 1 (SIK1) gene was associated with hypertension. Lower SIK1 activity in vascular smooth muscle cells (VSMCs) leads to decreased sodium-potassium ATPase activity, which associates with increased vascular tone. Also, SIK1 participates in a negative feedback mechanism on the transforming growth factor-β1 signaling and downregulation of SIK1 induces the expression of extracellular matrix remodeling genes.Objective: To evaluate whether reduced expression/activity of SIK1 alone or in combination with elevated salt intake could modify the structure and function of the vasculature, leading to higher blood pressure. Methods and Results: SIK1 knockout (sik1 −/−) and wild-type (sik1 +/+ ) mice were challenged to a normal-or chronic high-salt intake (1% NaCl). Under normal-salt conditions, the sik1 −/− mice showed increased collagen deposition in the aorta but similar blood pressure compared with the sik1 +/+ mice. During high-salt intake, the sik1 +/+ mice exhibited an increase in SIK1 expression in the VSMCs layer of the aorta, whereas the sik1 −/− mice exhibited upregulated transforming growth factor-β1 signaling and increased expression of endothelin-1 and genes involved in VSMC contraction, higher systolic blood pressure, and signs of cardiac hypertrophy. In vitro knockdown of SIK1 induced upregulation of collagen in aortic adventitial fibroblasts and enhanced the expression of contractile markers and of endothelin-1 in VSMCs. Conclusions: Bertorello et al SIK1, Hypertension, and Vascular Remodeling 643Elevated arterial blood pressure can occur as a consequence of increased vascular stiffness attributed to both extracellular matrix deposition/remodeling and enhanced contractility/stiffness of VSMCs. [10][11][12][13] Transforming growth factor-β1 (TGF-β1) is a pleiotropic cytokine that mediates extracellular matrix remodeling processes within the vasculature in addition to promote VSMCs differentiation toward a contractile phenotype.14-18 SIK1 participates in a negative feedback mechanism on the TGF-β1 signaling pathway. 19 We have reported that in epithelial cells the loss of SIK1 increased the expression of SNAI2 and TWIST1, known transcription factors involved in fibrosis and extracellular matrix remodeling. Recently, brain SIK1 activity has been shown to be relevant for blood pressure regulation in rodents by regulating sympathetic activity. Higher hypothalamic activity of SIK1 was associated with reduced sympathoexcitatory activity and lower arterial blood pressure in rats after a high-salt diet and intracerebroventricular infusion of Na + . 20Because SIK1 is present in the vasculature and lower SIK1 activity was associated with elevated blood pressure in humans and rodents, we hypothesize that the lack of SIK1 could trigger vascular remodeling processes leading to increased vascular stiffness and consequently to higher blood pressure. Furthermore, these events alone or in combination with other risk factors (high-s...

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Microarray analysis of differentially expressed genes in ovarian and fallopian tube epithelium from risk‐reducing salpingo‐oophorectomies

Veskimäe

Staff

Tabaro

et al. 2015

Genes Chromosomes & Cancer

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Mutations in the BRCA1 and BRCA2 genes confer an increased lifetime risk for breast and ovarian cancer. Ovarian cancer risk can be decreased by risk-reducing salpingo-oophorectomy (RRSO). Studies on RRSO material have altered the paradigm of serous ovarian cancer pathogenesis. The purpose of this study was to identify candidate genes possibly involved in the pathogenesis of serous ovarian cancer by carrying out a microarray analysis of differentially expressed genes in BRCA1/2- mutation positive ovarian and fallopian tube epithelium derived from RRSO surgery. Freshly frozen ovarian and fallopian tube samples from nine BRCA1/2 mutation carriers scheduled for RRSO were prospectively collected together with five mutation-negative control patients undergoing salpingo-oophorectomy for benign indications. Microarray analysis of genome-wide gene expression was performed on ovarian and fallopian tube samples from the BRCA1/2 and control patients. The validation of microarray data was performed by quantitative real-time polymerase chain reaction (qRT-PCR) in selected cases of RRSO samples and also in high grade serous carcinoma samples collected from patients with a BRCA phenotype. From 22,733 genes, 454 transcripts were identified that were differentially expressed in BRCA1/2 mutation carriers when compared with controls, pooling all ovarian and fallopian tube samples together. Of these, 299 genes were statistically significantly downregulated and 155 genes upregulated. Differentially expressed genes in BRCA1/2 samples reported here might be involved in serous ovarian carcinogenesis and provide interesting targets for further studies.

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Salt‐inducible kinase 1 regulates E‐cadherin expression and intercellular junction stability

Cited by 30 publications

References 40 publications

Inositol pyrophosphates promote tumor growth and metastasis by antagonizing liver kinase B1

Inositol pyrophosphates promote tumor growth and metastasis by antagonizing liver kinase B1

Increased Arterial Blood Pressure and Vascular Remodeling in Mice Lacking Salt-Inducible Kinase 1 (SIK1)

Microarray analysis of differentially expressed genes in ovarian and fallopian tube epithelium from risk‐reducing salpingo‐oophorectomies

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