Protein kinase C-dependent and -independent activation of Na+/H+ exchanger by G alpha 12 class of G proteins.

Dhanasekaran, N.; Prasad, Mona; Wadsworth, Sandra J.; Dermott, Jonathan M.; Rossum, Gerda van

doi:10.1016/s0021-9258(17)32643-1

Cited by 105 publications

(3 citation statements)

References 39 publications

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“…In general, the immediate effectors coupled to the G 12 family are unknown. They have been implicated in transduction of thrombin receptor activation of AP-1 mediated gene expression [57] activation of Jun Kinase / stress activated protein kinase and activation of different isoforms of a growth factor -responsive Na + /H + exchanger (NHE) present in most cells [58,59].…”

Section: Discussionmentioning

confidence: 99%

Investigation of the role of the carboxyl-terminal tails of the α and β isoforms of the human thromboxane A2 receptor (TP) in mediating receptor:effector coupling

Walsh

Foley

Kinsella

2000

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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We have investigated the functional coupling of alpha and beta isoforms of the human thromboxane A(2) receptor (TP) to Galpha(16) and Galpha(12) members of the G(q) and G(12) families of heterotrimeric G proteins in human embryonic kidney (HEK) 293 cell lines HEK.alpha10 or HEK.beta3, stably over-expressing TPalpha and TPbeta, respectively. Moreover, using HEK.TP(Delta328) cells which over-express a variant of TP truncated at the point of divergence of TPalpha and TPbeta, we investigated the requirement of the C-tail per se in mediating G protein coupling and effector activation. Both TPalpha and TPbeta couple similarly to Galpha(16) to affect increases in inositol 1,4,5-trisphosphate (IP(3)) and mobilisation of intracellular calcium ([Ca(2+)](i)) in response to the TP agonist U46619. Whilst both TP isoforms mediated [Ca(2+)](i) mobilisation in cells co-transfected with Galpha(12), neither receptor generated corresponding increases in IP(3), indicating that the Galpha(12)-mediated increases in [Ca(2+)](i) do not involve PLC activation. Verapamil, an inhibitor of voltage dependent Ca(2+) channels, reduced [Ca(2+)](i) mobilisation in TPalpha and TPbeta cells co-transfected with Galpha(12) to approximately 40% of that mobilised in its absence, whereas [8-(N,N-diethylamino)-octyl-3,4, 5-trimethoxybenzoate, hydrochloride] (TMB-8), an antagonist of intracellular Ca(2+) release, had no effect on [Ca(2+)](i) mobilisation by either receptor isoform co-transfected with Galpha(12). Despite the lack of differential coupling specificity by TPalpha and TPbeta, TP(Delta328) signalled more efficiently in the absence of a co-transfected G protein compared to the wild type receptors but, on the other hand, displayed an impaired ability to couple to co-transfected Galpha(11), Galpha(12) or Galpha(16) subunits. In studies investigating the role of the C-tail in influencing coupling to the effector adenylyl cyclase, similar to TPalpha but not TPbeta, TP(Delta328) coupled to Galpha(s), leading to increased adenosine 3',5'-cyclic monophosphate (cAMP), rather than to Galpha(i). Whereas TP(Delta328) signalled more efficiently in the absence of co-transfected G protein compared to the wild type TPalpha, co-transfection of Galpha(s) did not augment cAMP generation by TP(Delta328). Hence, from these studies involving the wild type TPalpha, TPbeta and TP(Delta328), we conclude that the C-tail sequences of TP are not a major determinant of G protein coupling specificity to Galpha(11) and Galpha(16) members of the G(q) family or to Galpha(12); it may play a role in determining G(s) versus G(i) coupling and may act as a determinant of coupling efficiency.

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Section: Discussionmentioning

confidence: 99%

Investigation of the role of the carboxyl-terminal tails of the α and β isoforms of the human thromboxane A2 receptor (TP) in mediating receptor:effector coupling

Walsh

Foley

Kinsella

2000

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…For R 12 , the immediate downstream effector is not known (4, 47). R 12 can activate the Na/H exchanger and kinase pathways but probably not directly (10,12,48). Expression of either the wild-type or constitutively active R 12 causes neoplastic transformation that is a sensitive end point for activation of an R 12 -mediated cascade (45,49).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, microinjection of antibodies to G 12 inhibit thrombinstimulated DNA synthesis (9). The proximal downstream effectors of these proteins are not known but studies have shown G 12 /G 13 effects on phospholipase A2 (6), the Na/H exchanger (10,11), the Jun kinase/stress-activated protein kinase pathway (12), EGF-stimulated MAP kinase activity (8), stress fiber formation and focal adhesion assembly (13), and AP-1-mediated transcriptional activity (9). Receptor coupling to G 12 /G 13 has been shown for the thrombin, thromboxane A2 (14), bradykinin (15), and TSH receptors (16), with other receptors yet to be identified.…”

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confidence: 99%

Gα₁₂ Requires Acylation for Its Transforming Activity

Jones

Gutkind

1998

Biochemistry

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The alpha subunit of the heterotrimeric G protein G12, harboring a mutation in the GTP binding domain (Q229L), behaves as a potent oncogene in NIH 3T3 cells. This alpha subunit, like most other G protein alpha subunits, undergoes palmitoylation, the reversible posttranslational addition of palmitate to cysteine residues. We investigated the role of palmitoylation of alpha12 in membrane localization and transformation efficiency and whether another lipid modification, myristoylation, could substitute for palmitoylation. NIH 3T3 cells were stably transfected with plasmids that expressed the wild-type alpha12, the constitutively active Q229L (QL) mutant, and mutants in which C11 was changed to S (C11S) and S2 and R6 were changed to G and S, respectively (S2G). Incorporation of [3H]palmitate was found in the endogenous and expressed alpha12 but not in the C11S mutants. Incorporation of [3H]myristate was found only in the S2G mutants. The wild type, QL mutant, and all the acylation mutants were found in the particulate fraction. Cells expressing the nonpalmitoylated C11S,QL mutant did not undergo transformation. The S2G mutation in the nonpalmitoylated C11S,QL mutant restored the transformation efficiency to a greater level than that of the palmitoylated QL mutant as measured by foci formation, growth in soft agar, and growth rate. Palmitoylation was critical for the transformation efficiency of alpha12 but not specifically required because myristoylation could substitute for these functions.

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G-protein regulatory pathways: Rocketing into the twenty-first century

Knall¹,

Johnson²

1998

J. Cell. Biochem.

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Complex cellular responses involve the integration of heterotrimeric G protein systems with protein kinase signal transduction pathways. Key in this integration is the control of small GTP-binding proteins including Ras and Rho family members. In this paper, we discuss the control of signal transduction pathways by G proteins and their integration with specific tyrosine kinases. The integration of G proteins, kinases, and small GTP-binding proteins in controlling cellular responses is illustrated through the newly defined Gα -regulated pathways. Furthermore, the polymorphonuclear leukocyte provides a primary cell system for analyzing the integration of G proteins, kinases, and small GTP-binding proteins in controlling cellular functions such as superoxide production, adherence, chemotaxis, and granule secretion. J. Cell. Biochem. Suppls. 30/31:137-146, 1998. © 1998 Wiley-Liss, Inc.

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Protein kinase C-dependent and -independent activation of Na+/H+ exchanger by G alpha 12 class of G proteins.

Cited by 105 publications

References 39 publications

Investigation of the role of the carboxyl-terminal tails of the α and β isoforms of the human thromboxane A2 receptor (TP) in mediating receptor:effector coupling

Investigation of the role of the carboxyl-terminal tails of the α and β isoforms of the human thromboxane A2 receptor (TP) in mediating receptor:effector coupling

Gα₁₂ Requires Acylation for Its Transforming Activity

G-protein regulatory pathways: Rocketing into the twenty-first century

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Protein kinase C-dependent and -independent activation of Na+/H+ exchanger by G alpha 12 class of G proteins.

Cited by 105 publications

References 39 publications

Investigation of the role of the carboxyl-terminal tails of the α and β isoforms of the human thromboxane A2 receptor (TP) in mediating receptor:effector coupling

Investigation of the role of the carboxyl-terminal tails of the α and β isoforms of the human thromboxane A2 receptor (TP) in mediating receptor:effector coupling

Gα12 Requires Acylation for Its Transforming Activity

G-protein regulatory pathways: Rocketing into the twenty-first century

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Gα₁₂ Requires Acylation for Its Transforming Activity