Current Faculty

Stephen Lanier, PhD

Lanier PictureProfessor
Associate Provost for Research

Education
1982         Ph.D.,
University of Tennessee Center for Health Sciences

Contact Info
laniersm@musc.edu
Tel: 843-792-0442
Fax: 843-792-5110
Office: COL 207

Research Interests

Accessory Proteins for G-Protein Signaling Systems

G-proteins are one of the most widely used mechanisms in nature for transducing signals from the extracellular to the intracellular environment.

Accessory proteins that interact with and regulate G-proteins offer unexpected and surprising mechanisms for signal input to G-protein signaling systems.

OVERALL HYPOTHESIS: Signaling efficiency/specificity for heterotrimeric G-protein systems is determined in part by accessory proteins which regulate the efficiency and/or specificity of signal transfer from G-protein coupled receptors (GPCRs) to G-proteins, segregate a signaling complex to microdomains of the cell, regulate the basal activity of the system and/or provide alternative modes of signal input to G-protein signaling systems that operate independent of a typical GPCR.

Relative to this hypothesis our long-term objectives are to define such accessory proteins, their mechanism of regulation, their dysfunction in various diseases and their potential as therapeutic targets and diagnostic tools.

We developed a series of experimental approaches to identify such accessory proteins. One approach was based upon protein interaction strategies with receptor subdomains. A second approach was based upon the functionality of the system and was designed to identify novel proteins that directly regulate the activation state of G-protein. The latter approach led to the discovery of Activators of G-protein signaling (AGS) 1-13. AGS proteins interact with different subunits and/or conformations of heterotrimeric G-proteins and selectively regulate different types of G-proteins.

Activators of G-protein signaling define three primary groups of proteins that include guanine nucleotide exchange factors, guanine nucleotide dissociation inhibitors and proteins that interact with Gbg.    The discovery of AGS proteins and related entities led to the realization that Gα and Gbg may exist complexed with alternative binding partners independent of the classical Gαβγ heterotrimer and that Gα and Gbg are processing signals within the cell distinct from their role as transducers for cell surface GPCRs, including protein trafficking, mitotic spindle dynamics and organelle function.

AGS proteins and related entities play unexpected and important functional roles in a number of systems and impact a number of signaling pathways that influence system adaptation, cell growth and differentiation.  Rapidly accumulating data from disease tissue profiling and genome-based technologies suggest that selected AGS proteins play a role in specific diseases and are thus candidate signaling modules for therapeutic targeting.  AGS1 (RasD1), which is growth inhibitory, is consistently down-regulated in various cancers.   Renal AGS3 (GPSM1) is markedly elevated in polycystic kidney disease and in response to renal injury.   In cell culture, AGS3 traffics into the aggresome pathway and it also increases autophagy.  AGS2 (Tctex1), AGS3 and AGS5 (GPSM2, LGN) are involved in cell differentiation. AGS7 (TRIP13) was identified as a thyroid receptor interacting protein and AGS8 (FNDC1) promotes apoptosis of cardiac myocytes.

Group II AGS proteins are of particular interest with each member of this group containing one to four G-protein Regulatory  (GPR) motifs that interact with Gai/o-GDP and/or Gat-GDP.  Thus, Gai-GDP can complex with a GPR motif free of Gbg and this complex is an apparent target for non-receptor GEFs in a manner similar to the regulation of Gabg by cell-surface GPCRs.  Recent data suggest that the Gai-GPR signaling complex is also regulated by cell-surface GPCRs providing an unexpected opportunity for signal integration.  

The unexpected mechanisms for regulation of G-protein signaling systems that are operative for AGS proteins and the expanded functional roles for this important signaling system may provide new opportunities for both diagnostics and pharmacological intervention.

Recent Publications | Additional Publications

1.  Blumer JB, Oner SS, Lanier SM. Group II activators of G-protein signalling and proteins containing a G-protein regulatory motif. Acta Physiol (Oxf). 2011 May 25. doi: 10.1111/j.1748-1716.2011.02327.x. PMID: 21615707

2.  Sato M, Hiraoka M, Suzuki H, Bai Y, Kurotani R, Yokoyama U, Okumura S, Cismowski MJ, Lanier SM, Ishikawa Y. Identification of transcription factor E3 (TFE3) as a receptor-independent activator of Gα16: gene regulation by nuclear Gα subunit and its activator. J Biol Chem. 2011 May 20;286(20):17766-76. Epub 2011 Mar 24. PMID:21454667

3.  Regner KR, Nozu K, Lanier SM, Blumer JB, Avner ED, Sweeney WE Jr, Park F. Loss of activator of G-protein signaling 3 impairs renal tubular regeneration following acute kidney injury in rodents. FASEB J. 2011 Jun;25(6):1844-55. Epub 2011 Feb 22. PMID:21343176

4.  Chan P, Gabay M, Wright FA, Kan W, Oner SS, Lanier SM, Smrcka AV, Blumer JB, Tall GG. Purification of heterotrimeric G protein alpha subunits by GST-Ric-8 association: primary characterization of purified G alpha(olf). J Biol Chem. 2011 Jan 28;286(4):2625-35. Epub 2010 Nov 29. PMID:21115479

5.  Oner SS, An N, Vural A, Breton B, Bouvier M, Blumer JB, Lanier SM. Regulation of the AGS3·G{alpha}i signaling complex by a seven-transmembrane span receptor. J Biol Chem. 2010 Oct 29;285(44):33949-58. Epub 2010 Aug 17. PMID: 20716524

6.  Nadella R, Blumer JB, Jia G, Kwon M, Akbulut T, Qian F, Sedlic F, Wakatsuki T, Sweeney WE Jr, Wilson PD, Lanier SM, Park F. Activator of G protein signaling 3 promotes epithelial cell proliferation in PKD.  J Am Soc Nephrol. 2010 Aug;21(8):1275-80. Epub 2010 May 20. PMID:20488951

7.  Vural  A, Oner S, An N, Simon V, Ma Z, Blumer JB and Lanier SM. (2010) Distribution of Activator of G-protein Signaling 3 within the aggresomal pathway: the role of specific residues in the tetratricopeptide repeat domain and  differential regulation by the AGS3 binding partners Gialpha and mammalian Inscuteable. Molecular and Cellular Biology 30:1528-40


Books and Monographs 

Blumer JB, Smrcka AV and Lanier SM. (2007) “Mechanistic pathways and biological roles for receptor-independent activators of G-protein signaling.” Pharmacology and Therapeutics. Editors David Sibley and Jurgen Wess.

Blumer JB, Sato M and Lanier SM. (2007) AGS3. UCSD-Nature Molecule Pages. Published online: 27 Nov 2007 http://www.signaling-gateway.org/molecule/query?afcsid=A000228

Lanier SM, Struckhoff AP and Cismowski MJ. (2007) AGS1. UCSD-Nature Molecule Pages. Published online: 21 Nov 2007 http://www.signaling-gateway.org/molecule/query?afcsid=A000226

Sato M, Blumer JB, Simon V and Lanier SM. (2006) “Accessory proteins for G proteins: Partners in signaling.” Annual Review of Pharmacology and Toxicology 46:151-87.

 
 
 

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