Cripto stabilizes GRP78 on the cell membrane

Kouznetsova, Valentina L.; Hu, Hannah; Teigen, Knut; Zanetti, Maurizio; Tsigelny, Igor F.

doi:10.1002/pro.3358

Cited by 13 publications

(7 citation statements)

References 21 publications

(46 reference statements)

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“…Proline-rich region plays important roles in mediating protein-protein interactions, and the specificity of interactions can be finely tuned by the proline-rich sequence [31]. On the cell surface, GRP78 largely exists as a peripheral protein [10] and associates with GPI-anchored [11], [32], [33] or transmembrane partner proteins [18], [34], [35]. Since the PRR is essential for GRP78 to form complex with CD44v, we hypothesized that the COOH-terminal PRR of GRP78 may be critical for its cell surface expression through its ability to form complex with partner proteins such as CD44v.…”

Section: Resultsmentioning

confidence: 99%

The COOH-Terminal Proline-Rich Region of GRP78 Is a Key Regulator of Its Cell Surface Expression and Viability of Tamoxifen-Resistant Breast Cancer Cells

2019

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Translocation of 78-kDa glucose-regulated protein (GRP78) from endoplasmic reticulum (ER) to plasma membrane represents a paradigm shift beyond its traditional function as an ER chaperone protein. Cell surface GRP78 (csGRP78) exerts novel signaling functions, and mechanisms underlying its cell surface expression are just emerging. Acquired tamoxifen resistance of breast cancer cells is accompanied with elevated level of csGRP78. Therefore, the tamoxifen-resistant MCF7 breast cancer cells (MCF7-LR) represents a clinically relevant model to study mechanisms of csGRP78 expression. We discovered that a proline-rich region (PRR) containing three consecutive prolines close to the COOH-terminus of GRP78 is important for its ability to form a complex with the partner protein, CD44v, as demonstrated by in vitro glutathione S -transferase pull-down assay. Proline to alanine mutations at the PRR compromised GRP78 expression level on the cell surface as evidenced by purification of biotinylated cell surface proteins. Reconstitution of MCF7-LR cells with the PRR mutant after knockdown of endogenous GRP78 diminished the capacity of GRP78 to stimulate STAT3 activation. The enforced expression of a short peptide bearing the PRR region of GRP78 led to reduction of CD44v and Cyclin D1 protein levels as well as cell viability, accompanied with increase in apoptotic signaling including cleaved Caspase-3 and PARP. These findings suggest that the COOH-terminal PRR of GRP78 is critical for its interaction with CD44v as well as its cell surface expression, and enforced expression of the short peptide bearing the PRR region may provide a new approach to lower the viability of tamoxifen-resistant breast cancer cells.

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Section: Resultsmentioning

confidence: 99%

The COOH-Terminal Proline-Rich Region of GRP78 Is a Key Regulator of Its Cell Surface Expression and Viability of Tamoxifen-Resistant Breast Cancer Cells

2019

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“…GRP78, as an endoplasmic reticulum resident and chaperone molecule, is a major regulator of ERS response ( 47 ). GRP78 regulates the activation of three ER transmembrane binding sensors, IRE1α, cyclic AMP-dependent transcription factor ATF-6 α (ATF6) and PERK, via PERK/eIF-2α and IRE1α or ATF6/XBP-1s axes, which are two branches of the unfolded protein response (UPR), affecting the expression of CHOP ( 48 ). CHOP was revealed to regulate several pro- and anti-apoptotic genes including Bcl-2, tribbles related protein 3 (TRB3) and growth arrest and DNA damage-inducible protein 34 (GADD34), which are target genes of CHOP ( 49 ).…”

Section: Discussionmentioning

confidence: 99%

Milk‑derived hexapeptide PGPIPN prevents and attenuates acute alcoholic liver injury in mice by reducing endoplasmic reticulum stress

Chen

et al. 2020

Int J Mol Med

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Bioactive peptides are an emerging area of biomedical research in the study of numerous human diseases, including acute alcoholic liver injury (AALI). To study the role and mechanism of the milk-derived hexapeptide Pro-Gly-Pro-Ile-Pro-Asn (PGPIPN) in preventing and reducing AALI, the present study established a mouse model of AALI. PGPIPN was used as a therapeutic drug, and glutathione (GSH) was used as a positive control. The body and liver weights of mice were measured, and the liver indexes were calculated to observe mice health. The pathological morphology of liver tissues stained with hematoxylin and eosin were examined to analyze hepatic injury, and hepatocyte apoptosis was measured with a TUNEL assay. The concentrations or activities of alanine aminotransferase (ALT), aspartate aminotransferase, tumor necrosis factor-α, interleukin (IL)-1β, IL-6, triglyceride, total cholesterol, malondialdehyde, superoxide dismutase and GSH peroxidase (GSH-PX) were detected in serum and/or liver homogenates. The 78 kDa glucose-regulated protein (GRP78), protein kinase R-like (PKR) endoplasmic reticulum kinase (PERK), phosphorylated (p)-PERK, eukaryotic initiation factor 2α (eIF-2α), p-eIF-2α, inositol-requiring enzyme 1α (IRE-1α), spliced X-box binding protein 1 (XBP-1s), C/EBP homologous protein (CHOP), caspase-3 and cleaved caspase-3 proteins associated with endoplasmic reticulum stress in hepatocytes were assessed by western blotting, and RNA levels of XBP-1s, CHOP and caspase-3 genes were assessed by reverse transcription-quantitative PCR. The results suggested that PGPIPN attenuated alcoholic hepatocyte damage in animal models and reduced hepatocyte oxidative stress in a dose-dependent manner. Moreover, PGPIPN reduced endoplasmic reticulum stress by regulating the expression levels of p-PERK, p-eIF-2α, XBP-1s, CHOP, caspase-3 and cleaved caspase-3. Collectively, the present results indicated that PGPIPN, as a potential therapeutic drug for AALI, exerted a protective effect on the liver and could reduce liver damage.

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“…Nodal can independently bind to ALK7, but is greatly potentiated by Cripto‐1; in which case ALK7 will only complex with ActRIIB, but not with ActRIIA 213 . Independent of its co‐receptor activities, Cripto‐1 also inhibits TGF‐β1, Activin A, and Activin B signaling when interacting with glucose‐regulated protein‐78 (GRP78) at the cell surface via its CFC domain, 216,217 which helps stabilize GRP78 at the surface 218 . Outside of its role in TGF‐β superfamily signaling, Cripto‐1 has been found to enhance Notch and Wnt signaling, and in its soluble form, Cripto‐1 can activate the Src, PI3K/Akt, and MAPK pathways through its interactions with the heparan sulfate proteoglycan Glypican‐1 219 .…”

Section: Tgf‐β Superfamily Co‐receptors and Their Role In Cancermentioning

confidence: 99%

TGF‐β superfamily co‐receptors in cancer

Pawlak

Blobe

2021

Developmental Dynamics

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Transforming growth factor‐β (TGF‐β) superfamily signaling via their cognate receptors is frequently modified by TGF‐β superfamily co‐receptors. Signaling through SMAD‐mediated pathways may be enhanced or depressed depending on the specific co‐receptor and cell context. This dynamic effect on signaling is further modified by the release of many of the co‐receptors from the membrane to generate soluble forms that are often antagonistic to the membrane‐bound receptors. The co‐receptors discussed here include TβRIII (betaglycan), endoglin, BAMBI, CD109, SCUBE proteins, neuropilins, Cripto‐1, MuSK, and RGMs. Dysregulation of these co‐receptors can lead to altered TGF‐β superfamily signaling that contributes to the pathophysiology of many cancers through regulation of growth, metastatic potential, and the tumor microenvironment. Here we describe the role of several TGF‐β superfamily co‐receptors on TGF‐β superfamily signaling and the impact on cellular and physiological functions with a particular focus on cancer, including a discussion on recent pharmacological advances and potential clinical applications targeting these co‐receptors.

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Cripto stabilizes GRP78 on the cell membrane

Cited by 13 publications

References 21 publications

The COOH-Terminal Proline-Rich Region of GRP78 Is a Key Regulator of Its Cell Surface Expression and Viability of Tamoxifen-Resistant Breast Cancer Cells

The COOH-Terminal Proline-Rich Region of GRP78 Is a Key Regulator of Its Cell Surface Expression and Viability of Tamoxifen-Resistant Breast Cancer Cells

Milk‑derived hexapeptide PGPIPN prevents and attenuates acute alcoholic liver injury in mice by reducing endoplasmic reticulum stress

TGF‐β superfamily co‐receptors in cancer

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