The Prolyl Peptidases PRCP/PREP Regulate IRS-1 Stability Critical for Rapamycin-induced Feedback Activation of PI3K and AKT

Duan, Lei; Ying, Guoguang; Danzer, Brian; Perez, Ricardo E.; Shariat‐Madar, Zia; Levenson, Victor; Maki, Carl G.

doi:10.1074/jbc.m114.550038

Cited by 18 publications

(25 citation statements)

References 44 publications

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“…Regarding the constituents of JSD, Rhubarb is a herb commonly used in traditional medicine for diarrhea, removing stagnancy, heat clearing, fire draining, detoxicating, promoting blood circulation, and removing blood stasis; therefore, this herb is useful for clearing heat and relieving turbidity in DN. The literature [14,23,24] has reported that this herb has good antidiabetic effects. Liquorice is a sweet-natured herb and is clinically applied as a classical adjuvant herb in many prescriptions.…”

Section: Discussionmentioning

confidence: 99%

Jowiseungki decoction affects diabetic nephropathy in mice through renal injury inhibition as evidenced by network pharmacology and gut microbiota analyses

Meng

Kang

et al. 2020

Chin Med

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Background: Jowiseungki decoction (JSD) is a prescription commonly used for the treatment of diabetic complications or diabetic nephropathy (DN) in traditional medicine clinics. However, the underlying therapeutic mechanisms of JSD are still unclear. Methods: Streptozotocin (STZ)-induced DN mice were administered 100 and 500 mg/kg JSD for 4 weeks, and the therapeutic mechanisms and targets of JSD were analyzed by network pharmacology and gut microbiota analyses. Results: JSD significantly decreased the increase in food and water intake, urine volume, fasting blood glucose, serum glucose and triglyceride levels, and urinary albumin excretion. JSD administration significantly increased the decrease in insulin secretion and creatinine clearance and reduced the structural damage to the kidney tissues. Moreover, JSD administration significantly inhibited the expression of protein kinase C-alpha (PKC-α), transforming growth factor beta-1 (TGF-β1), α-smooth muscle actin (α-SMA), nuclear factor-κB (NF-κB), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) in the kidney tissues of DN mice, while it significantly increased the phosphorylation of insulin receptor substrate 1 (IRS-1), phosphatidylinositol-3-kinase (PI3K), and protein kinase B (Akt). In the network pharmacological analysis, JSD obviously influenced phosphatase binding, protein serine/threonine kinase, and mitogen-activated protein kinase (MAPK)-related signaling pathways. Our data suggest that JSD can improve symptoms in STZ-induced DN mice through the inhibition of kidney dysfunction, in particular, by regulating the PKCα/PI3K/Akt and NF-κB/α-SMA signaling pathways. Gut microbiota analysis can help to discover the pharmacomechanisms of the influence of JSD on bacterial diversity and flora structures in DN. Conclusion: JSD can improve the symptoms of DN, and the underlying mechanism of this effect is renal protection through the inhibition of fibrosis and inflammation. JSD can also change bacterial diversity and community structures in DN.

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Section: Discussionmentioning

confidence: 99%

Jowiseungki decoction affects diabetic nephropathy in mice through renal injury inhibition as evidenced by network pharmacology and gut microbiota analyses

Meng

Kang

et al. 2020

Chin Med

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“…There is increasing evidence that IRS-1 is an important growth-regulatory adaptor molecule which plays a role in cell proliferation. Prolylcarboxypeptidase and prolylendopeptidase-mediated stabilization of IRS1 is critical for PI3K/Akt signaling is associated with development and clinical aggressiveness of pancreatic cancer (48). Moreover, IRS1 is highly expressed in localized breast tumors and regulates the sensitivity of breast cancer cells to chemotherapy (49).…”

Section: Discussionmentioning

confidence: 99%

“…Insulin stimulation partially inhibits IRS1-CD36 association via decrease of CD36 ubiquitination, which leads to IRS1-CUL7 interaction and IRS1 degradation. In the absence of CD36 or expression of CD36-K/A which does not bind to IRS1 well, IRS1 interaction with CUL7 was enhanced, leading to accelerated by guest on May 8, 2018 …”

Section: Figure 3 Cd36 Alleviates Insulin-induced Degradation Of Irs-1mentioning

confidence: 99%

“…IRS1 not only plays an important role in by guest on May 8, 2018 http://www.jbc.org/ relaying insulin stimulation to the activation of PI3K/Akt pathway, but also provides a site of negative-feedback regulation to terminate signaling by undergoing insulin-stimulated ubiquitination and proteasomal degradation. We examined whether IRS1 plays a role in the observed protective effect of CD36 on insulininduced insulin resistance and found that IRS1 level is higher in the presence of CD36 in myotubes following insulin treatment (Fig.…”

Section: Cd36 Protects Irs1 From Insulin-induced Proteasomal Degradationmentioning

confidence: 99%

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Ubiquitinated CD36 sustains insulin-stimulated Akt activation by stabilizing insulin receptor substrate 1 in myotubes

Sun

Tan

Huang

et al. 2018

Journal of Biological Chemistry

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Both the magnitude and duration of insulin signaling are important in executing its cellular functions. Insulin-induced degradation of insulin receptor substrate 1 (IRS1) represents a key negative feedback loop that restricts insulin signaling. Moreover, high concentrations of fatty acids (FAs) and glucose involved in the etiology of obesity-associated insulin resistance also contribute to the regulation of IRS1 degradation. The scavenger receptor CD36 binds many lipid ligands and its contribution to insulin resistance has been extensively studied, but the exact regulation of insulin sensitivity by CD36 is highly controversial. Herein, we found that CD36 knockdown in C2C12 myotubes accelerated insulin-stimulated Akt activation, but the activated signaling was sustained for a much shorter period of time as compared to wild type cells, leading to exacerbated insulin-induced insulin resistance. This was likely due to enhanced insulin-induced IRS1 degradation after CD36 knockdown. Overexpression of wild type CD36, but not a ubiquitination-defective CD36 mutant delayed Akt activation. We also found that CD36 functioned through ubiquitination-dependent binding to IRS1 and inhibiting its interaction with cullin 7, a key component of the multi-subunit cullin-RING E3 ubiquitin ligase complex. Moreover, dissociation of the Src family kinase Fyn from CD36 by free FAs or Fyn knockdown/inhibition accelerated insulin-induced IRS1 degradation, likely due to disrupted IRS1 interaction with CD36 and thus enhanced binding to cullin 7. In summary, we identified a CD36-dependent FA-sensing pathway that plays an important role in negative feedback regulation of insulin activation and may open up strategies for preventing or managing type 2 diabetes mellitus.Cell signaling is usually initiated by binding an activating ligand to a receptor on the plasma membrane (PM) that transmits the signal inside the cell. Distinct cellular responses and outcomes of a signaling pathway are achieved by precise regulation of its duration, magnitude and subcellular compartmentalization, which is mediated by an integrated network with multiple http://www.jbc.org/cgi

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“…The main function of POP was previously thought to be the preferential hydrolysis of peptides containing <30 amino acid residues in the extracellular space, such as substance P, thyrotropinreleasing hormone and gonadotrophin-releasing hormone (Friedman & Wilk, 1985;Toide, Okamiya, Iwamoto, & Kato, 1995). However, an increasing number of studies have shown that POP also plays important roles in many intracellular processes, such as the cell cycle (Sakaguchi, Matsuda, Matsumura, Yoshimoto, & Takaoka, 2011), signal transduction (Duan et al, 2014), protein maturation (Morawski et al, 2011), and intracellular transport (Morawski et al, 2011). POP also affects numerous pathological and physiological processes by regulating cell differentiation, proliferation, and apoptosis (Matsuda et al, 2013;Suzuki et al, 2014).…”

Section: Sf1 Contributes To the Regulation Of Progesterone Synthesimentioning

confidence: 99%

Prolyl oligopeptidase regulates progesterone secretion via the ERK signaling pathway in murine luteal cells

Bao

Zhang

et al. 2019

Molecular Reproduction Devel

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Prolyl oligopeptidase (POP), one of the most widely distributed serine endopeptidases, is highly expressed in the ovaries. However, the physiological role of POP in the ovaries is not clear. In this study, we investigated the significance of POP in the corpus luteum. Murine luteal cells were cultured in vitro and treated with a POP selective inhibitor, (2S)‐1[[(2 S)‐1‐(1‐oxo‐4‐phenylbutyl)‐2‐pyrrolidinyl carbonyl]‐2‐pyrrolidinecarbonitrile (KYP‐2047). We found that KYP‐2047 treatment decreased progesterone secretion. In contrast, POP overexpression increased progesterone secretion. Three essential steroidogenic enzymes, including p450 cholesterol side‐chain cleavage enzyme (CYP11A), 3β‐hydroxysteroid dehydrogenase (3β‐HSD), and the steroidogenic acute regulatory protein (StAR), were regulated by POP. Further studies showed that POP overexpression increased ERK1/2 phosphorylation and increased the expression of steroidogenic factor 1 (SF1), while KYP‐2047 treatment decreased ERK1/2 phosphorylation and SF1 expression. To clarify the role of ERK1/2 signaling in POP‐regulated progesterone synthesis, U0126‐EtOH, an inhibitor of the ERK signaling pathway, was used to treat luteal cells. We found that U0126‐EtOH decreased progesterone production and the expression of steroidogenic enzymes and SF1. POP overexpression did not reverse the effects of U0126‐EtOH. Overall, POP regulates progesterone secretion by stimulating the expression of CYP11A, 3β‐HSD, and StAR in luteal cells. ERK signaling and downstream SF1 expression contribute to this process.

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The Prolyl Peptidases PRCP/PREP Regulate IRS-1 Stability Critical for Rapamycin-induced Feedback Activation of PI3K and AKT

Cited by 18 publications

References 44 publications

Jowiseungki decoction affects diabetic nephropathy in mice through renal injury inhibition as evidenced by network pharmacology and gut microbiota analyses

Jowiseungki decoction affects diabetic nephropathy in mice through renal injury inhibition as evidenced by network pharmacology and gut microbiota analyses

Ubiquitinated CD36 sustains insulin-stimulated Akt activation by stabilizing insulin receptor substrate 1 in myotubes

Prolyl oligopeptidase regulates progesterone secretion via the ERK signaling pathway in murine luteal cells

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