IGPR-1 Is Required for Endothelial Cell–Cell Adhesion and Barrier Function

Wang, Yun Hwa Walter; Meyer, Rosana D.; Bondzie, Philip A.; Jiang, Yan; Rahimi, Ida; Rezazadeh, Kobra; Mehta, Manisha; Laver, Nora; Costello, Catherine E.; Rahimi, Nader

doi:10.1016/j.jmb.2016.11.003

Cited by 27 publications

(58 citation statements)

References 30 publications

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“…IGPR-1 is a cell adhesion molecule that mediates cell-cell adhesion and its activation regulates cell morphology and actin stress fiber alignment (24,43). The finding that IGPR-1 is activated by and regulates autophagy by stimulating activation of AMPK not only suggest a significant role for IGPR-1 in autophagy, but also links cell-cell adhesion to energy sensing and autophagy.…”

Section: Discussionmentioning

confidence: 99%

“…The following plasmids were all purchased from Addgene (Watertown, MA); pcDNA3.FLAG-ULK1 (Cat#27636), pMRX-IP-GFP-LC3-RFP (Cat#84573), pcDNA-IKKβ-FLAG (Cat#23298), pcDNA-IKKβ-A44 (Cat#23299), and constitutive active IKKβ (S177E S181E, Cat#11105). IGPR-1 constructs including wild-type IGPR-1 and Ser220 mutant, A220-IGPR-1 constructs were cloned into retroviral vector, pQCXIP with C-terminal Myc tag as previously described (18,24,45). Retroviruses were produced in 293-GPG cells as described (49).…”

Section: Methodsmentioning

confidence: 99%

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Cell adhesion molecule IGPR-1 activates AMPK connecting cell adhesion to energy sensing and autophagy

Amraei

Alwani

et al. 2020

Preprint

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Cellular stress caused by loss of extracellular matrix (ECM)-cell interaction involving integrins induces autophagy and autophagy is considered to protect cells from anoikis (i.e., cell death due to loss of cell adhesion). Immunoglobulin (Ig) and proline-rich receptor-1 (IGPR-1) is a newly identified cell adhesion molecule that mediates cell-cell adhesion and supports cell survival in response to anoikis.However, whether IGPR-1 is activated in response to and mediates autophagy is not known. In this study, we demonstrate that IGPR-1 is activated by autophagy inducing stimuli, such as nutrient deprivation, rapamycin and lipopolysaccharide (LPS). We have identified IκB kinaseβ (IKKβ) as a key serine/threonine kinase activated by autophagy stimuli and mediates phosphorylation of IGPR-1 at Ser220. Activation of IGPR-1, in turn, stimulates phosphorylation of AMP-activated protein kinase (AMPK), which leads to phosphorylation of key pro-autophagy proteins, ULK1 and Beclin-1, increased LC3-II levels and accumulation of LC3 punctum. This study demonstrates that IGPR-1 is activated by and regulates autophagy, connecting cell adhesion to autophagy, a finding that has important significance for autophagy-driven pathologies such cardiovascular diseases and cancer. Introduction:Autophagy (also called macroautophagy), the lysosomal degradation of cytoplasmic organelles or cytosolic components, is an evolutionarily conserved cytoprotective mechanism that is induced in response to cellular stress, such as nutrient withdrawal, loss of cell adhesion, and flow shear stress, or by therapeutic genotoxic agents and others 1, 2 . Cell-extracellular matrix (ECM) adhesion through engagement of cell adhesion molecules (CAMs) (e.g., integrins) is thought to regulate autophagy 3, 4 and more importantly loss of cell adhesion to ECM is linked to induction of autophagy 4, 5 .Upon autophagy, unc-51-like kinase 1 (ULK1 also known as ATG1) associates with autophagy-related protein 13 (ATG13), and focal adhesion kinase family interacting protein of 200 kD (FIP200) to form the ULK1 complex. ULK1 interaction with ATG13 and FIP200 is critical for ULK1 kinase activity and stability 6 .The ULK1 complex translocates to autophagy initiation sites and recruits the class III phosphatidylinositol 3-kinase, vacuolar protein sorting 34 (VPS34) complex consisting of BECLIN-1 (the mammalian orthologue of the yeast autophagy protein Apg6/Vps30 7 and multiple other ATGs leading to the phagophore formation 8 . The serine/threonine protein kinase mTOR (mechanistic target of rapamycin) complex 1 (mTORC1) is a key regulator of autophagy in response to nutrient availability. In the presence of amino acids, mTORC1 is activated and suppresses autophagy through phosphorylation of ULK1 and ATG13. However, upon nutrient deprivation, mTORC1 activity is inhibited leading to the activation of ULK1 that induces the autophagy program 9, 10 . Suppression of mTORC1 activity by AMP-activated protein kinase (AMPK) is central to regulation of autophagy. AMPK inactivates mTORC1 throu...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Cell adhesion molecule IGPR-1 activates AMPK connecting cell adhesion to energy sensing and autophagy

Amraei

Alwani

et al. 2020

Preprint

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“…The extracellular domain of CD28H contains an IgV-like domain and its cytoplasmic tail contains a proline rich motif that has been shown to interact with the SH3 domains of various proteins including SPIN90, CACNB2 and BPAG1. Initial studies identified CD28H as an adhesion molecule involved in cell-cell interaction, cell migration and angiogenesis [36,38] .…”

Section: Other Family Members Of Cd28/b7 Familymentioning

confidence: 99%

“…B7H7 possesses an IgV-IgC-IgV domain in its extracellular region [39] , and is expressed in intestines, breast, kidney, gallbladder, placenta and B cells [37,40] . B7H7 is believed to interact with CD28H via its first IgV domain and to send a co-stimulatory signal [37] , or co-inhibitory signal in the presence or absence of CD28H expression [38,41] . Aberrant expression of B7H7 has been observed in various cancer types including lung [42] osteosarcoma [43] and pancreatic cancers [44] .…”

Section: Other Family Members Of Cd28/b7 Familymentioning

confidence: 99%

CD28 family of receptors inter-connect in the regulation of T-cells

Krueger

Jules

Rieder³

et al. 2017

Receptor Clin Invest

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“…Transmembrane and immunoglobulin domain containing (TMIGD) family proteins are newly identified class of immunoglobulin (Ig) domain containing cell adhesion molecules (Ig-CAMs), which include TMIGD1, immunoglobulin and proline rich receptor-1 (IGPR-1) [10][11][12] and TMIGD3 13 , which also acts as a tumor suppressor 14 . Although originally described as a protector of renal epithelial cells from oxidative cell injury 15 , TMIGD1 is downregulated in human renal cancer and its re-expression in renal tumor cells inhibits cell proliferation, migration and tumor growth in mouse tumor xenograft 15 .…”

Section: Introductionmentioning

confidence: 99%

TMIGD1, a putative tumor suppressor, induces G2-M cell cycle checkpoint arrest in colon cancer cells

Koc

Amraei

et al. 2020

Preprint

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Colorectal cancer (CRC) is a leading non-familial cause of cancer mortality among men and women.Although various genetic and epigenetic mechanisms have been identified, the full molecular mechanisms deriving CRC tumorigenesis remains incompletely understood. In this study, we demonstrate that cell adhesion molecule transmembrane and immunoglobulin domain containing1 (TMIGD1) is highly expressed in mouse and human normal intestinal epithelial cells. We have developed TMIGD1 knockout mice and show that the loss of TMIGD1 in mice results in the development of adenomas in small intestine and colon. Additionally, the loss of TMIGD1 in mouse impaired intestinal epithelium brush border formation, junctional polarity and maturation. Mechanistically, TMIGD1 inhibits tumor cell proliferation, cell migration, arrests cell cycle at G2/M phase and induces expression of p 21CIP1 (cyclin-dependent kinase inhibitor 1), and p 27KIP1 (cyclin-dependent kinase inhibitor 1B) expression, key cell cycle inhibitor proteins involved in the regulation of the cell cycle. Moreover, we demonstrate that TMIGD1 is progressively downregulated in sporadic human CRC and correlates with poor overall survival. Our findings identify TMIGD1 as a novel tumor suppressor gene and provide insights into the pathogenesis of colorectal cancer and possibilities as a potential therapeutic target.

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IGPR-1 Is Required for Endothelial Cell–Cell Adhesion and Barrier Function

Cited by 27 publications

References 30 publications

Cell adhesion molecule IGPR-1 activates AMPK connecting cell adhesion to energy sensing and autophagy

Cell adhesion molecule IGPR-1 activates AMPK connecting cell adhesion to energy sensing and autophagy

CD28 family of receptors inter-connect in the regulation of T-cells

TMIGD1, a putative tumor suppressor, induces G2-M cell cycle checkpoint arrest in colon cancer cells

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