GRK2 suppresses lymphomagenesis by inhibiting the MALT1 proto-oncoprotein

Cheng, Jing; Klei, Linda R.; Hubel, Nathaniel E.; Zhang, Ming; Schairer, Rebekka; Maurer, Lisa M.; Klei, Hanna B.; Kang, Hongjun; Concel, Vincent J.; Delekta, Phillip C.; Dang, Eric V.; Mintz, Michelle A.; Baens, Mathijs; Cyster, Jason G.; Parameswaran, Narayanan; Thome, Margot; Lucas, Peter C.; McAllister-Lucas, Linda M.

doi:10.1172/jci97040

Cited by 12 publications

(11 citation statements)

References 85 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Emerging evidence indicates that GRK2 acts as an onco-modulator, influencing multiple cellular functions related to the hallmarks of cancer, such as cell proliferation, cell survival, cell motility, cell metabolism, and angiogenesis, via its impact on cancer-relevant signaling networks [ 45 , 46 ]. Our laboratory recently identified the proto-oncoprotein, MALT1 (Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1), as a novel binding partner of GRK2 [ 47 ]. In normal lymphocytes, stimulation of the B or T cell antigen receptor (AgR) results in assembly and activation of the “CBM” intracellular signaling complex, which is composed of the scaffolding protein CARMA1, the adaptor protein BCL10, and the protease MALT1 [ 48 , 49 ].…”

Section: Noncanonical Roles Of Grk2 In Lymphocytesmentioning

confidence: 99%

“…Our findings indicate that the N-terminal region of GRK2, comprised of a short helix (αN) followed by RH domain, binds to the MALT1 death domain (DD) [ 47 ]. When bound to MALT1, GRK2 inhibits MALT1-dependent NF-κB activation.…”

Section: Noncanonical Roles Of Grk2 In Lymphocytesmentioning

confidence: 99%

“…When bound to MALT1, GRK2 inhibits MALT1-dependent NF-κB activation. Notably, this N-terminal region of GRK2 is both necessary and sufficient for GRK2-mediated inhibition of MALT1 while the other domains within GRK2, such as the kinase and PH domains, are not required [ 47 ]. Interestingly, AgR stimulation, which promotes CBM complex assembly and MALT1 scaffolding and proteolytic activities, results in time-dependent dissociation of GRK2 and MALT1 in lymphocytes.…”

Section: Noncanonical Roles Of Grk2 In Lymphocytesmentioning

confidence: 99%

“…This is in contrast with the above-mentioned constitutive binding of GRK2 with the TCR CD3ε, which is not altered by antigen receptor stimulation [ 41 ]. While the impact of constitutive association of TCR CD3ε and GRK2 on downstream TCR-dependent signaling has not been investigated, our team found that GRK2 attenuates AgR-dependent CBM complex assembly, MALT1 scaffolding, and protease activity, NF-κB activation, and cytokine production in Jurkat T cells [ 47 ].…”

Section: Noncanonical Roles Of Grk2 In Lymphocytesmentioning

confidence: 99%

“…Further investigation unveiled a potential function of GRK2 as an onco-modulator/tumor suppressor by blocking MALT1 activity in MALT1-dependent lymphomas. First, we found that lower GRK2 mRNA expression is associated with significantly reduced survival in ABC-DLBCL [ 47 ]. Second, overexpression of GRK2 inhibits ABC-DLBCL cell proliferation while knockdown of GRK2 enhances ABC-DLBCL cell proliferation in vitro.…”

Section: Noncanonical Roles Of Grk2 In Lymphocytesmentioning

confidence: 99%

See 4 more Smart Citations

Canonical and Non-Canonical Roles of GRK2 in Lymphocytes

Cheng

Lucas

McAllister-Lucas

2021

Cells

Self Cite

View full text Add to dashboard Cite

G protein-coupled receptor kinase 2 (GRK2) is emerging as a key integrative signaling node in a variety of biological processes ranging from cell growth and proliferation to migration and chemotaxis. As such, GRK2 is now implicated as playing a role in the molecular pathogenesis of a broad group of diseases including heart failure, cancer, depression, neurodegenerative disease, and others. In addition to its long-known canonical role in the phosphorylation and desensitization of G protein-coupled receptors (GPCRs), recent studies have shown that GRK2 also modulates a diverse array of other molecular processes via newly identified GRK2 kinase substrates and via a growing number of protein-protein interaction binding partners. GRK2 belongs to the 7-member GRK family. It is a multidomain protein containing a specific N-terminal region (referred to as αN), followed by a regulator of G protein signaling homology (RH) domain, an AGC (Protein kinase A, G, C serine/threonine kinase family) kinase domain, and a C-terminal pleckstrin homology (PH) domain. GPCRs mediate the activity of many regulators of the immune system such as chemokines and leukotrienes, and thus GRK proteins may play key roles in modulating the lymphocyte response to these factors. As one of the predominant GRK family members expressed in immune cells, GRK2′s canonical and noncanonical actions play an especially significant role in normal immune cell function as well as in the development and progression of disorders of the immune system. This review summarizes our current state of knowledge of the roles of GRK2 in lymphocytes. We highlight the diverse functions of GRK2 and discuss how ongoing investigation of GRK2 in lymphocytes may inform the development of new therapies for diseases associated with lymphocyte dysregulation.

show abstract

Section: Noncanonical Roles Of Grk2 In Lymphocytesmentioning

confidence: 99%

Section: Noncanonical Roles Of Grk2 In Lymphocytesmentioning

confidence: 99%

Section: Noncanonical Roles Of Grk2 In Lymphocytesmentioning

confidence: 99%

Section: Noncanonical Roles Of Grk2 In Lymphocytesmentioning

confidence: 99%

Section: Noncanonical Roles Of Grk2 In Lymphocytesmentioning

confidence: 99%

See 3 more Smart Citations

Canonical and Non-Canonical Roles of GRK2 in Lymphocytes

Cheng

Lucas

McAllister-Lucas

2021

Cells

Self Cite

View full text Add to dashboard Cite

show abstract

Druggable Sphingolipid Pathways: Experimental Models and Clinical Opportunities

Blaho

2020

Druggable Lipid Signaling Pathways

View full text Add to dashboard Cite

Intensive research in the field of sphingolipids has revealed diverse roles in cell biological responses and human health and disease. This immense molecular family is primarily represented by the bioactive molecules ceramide, sphingosine, and sphingosine 1-phosphate (S1P). The flux of sphingolipid metabolism at both the subcellular and extracellular levels provides multiple opportunities for pharmacological intervention. The caveat is that perturbation of any single node of this highly regulated flux may have effects that propagate throughout the metabolic network in a dramatic and sometimes unexpected manner. Beginning with S1P, the receptors for which have thus far been the most clinically tractable pharmacological targets, this review will describe recent advances in therapeutic modulators targeting sphingolipids, their chaperones, transporters, and metabolic enzymes.

show abstract