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Adrian Clark DSc, FRCP, FMedSci
Professor of Medicine & Centre Lead for Endocrinology
Centre for Endocrinology

Contact Details:

a.j.clark@qmul.ac.uk

Professor Clark graduated in Medicine in 1976 and after training in general internal medicine worked as Registrar in Endocrinology at Hammersmith Hospital and Research Registrar at the Unit for Metabolic Medicine at Guys. He then began a period of five years training in molecular biology and receptor biology at the National Institutes of Health in Bethesda, USA working under Ira Pastan on the cloning of the EGF receptor and later under Kevin Catt on the angiotensin receptor. He was appointed to an MRC funded Senior Lectureship at Barts in 1991 where he established the Molecular Endocrinology laboratory. Professor Clark became Professor of Molecular Endocrinology in 1996 and Professor of Medicine in 2001. In addition to his role in the William Harvey, Professor Clark is Editor-in-Chief of the Journal of Endocrinology. He was awarded the Society for Endocrinology Medal in 1997 and the Clinical Endocrinology Trust Lectureship in 2007.

Current research interests

  • ACTH insensitivity
    We were the first to describe mutations in the ACTH receptor as a cause of Familial Glucocorticoid Deficiency (FGD), and more recently identified a second gene, MRAP, and partially inactivating mutations in STAR as additional causes of this syndrome. In collaboration with Angela Huebner’s group we identified the gene encoding ALADIN as the cause of a further form of ACTH insensitivity, the Triple A syndrome. At least three additional genes cause FGD and we are making good progress in identification of these genes which will reveal novel mechanisms of adrenocortical dysfunction.

  • MRAP and the melanocortin receptors
    MRAP was originally identified as the cause of FGD type 2 and we showed it to be the elusive accessory factor for expression and function of the melanocortin 2 receptor (MC2R; ACTH receptor). Investigation of its mechanism of action reveals it to function as a unique antiparallel homodimer which traffics with the MC2R to the cell surface. We identified an orthologue of MRAP which we have called MRAP2 which is expressed mainly in the hypothalamus, interacting with the MC3R and MC4R, and which appears to have novel regulatory roles with these receptors.

  • Growth and adult disease
    A longstanding interest in disorders of fetal and childhood growth has fostered interests in the mechanisms underlying the fetal origins of adult disease. At present we are undertaking a genome-wide analysis of epigenetic changes in models of programming – particular in relation to metabolic disturbances in the liver.


Key publications

 

  • Cooray SN, Do Vale IA, Leung K-Y, Webb T, Chapple JP, Cheetham ME, Elphick MR and Clark AJL. (2008) The Melanocortin 2 Receptor Accessory protein exists as a homodimer and is essential for the function of the Melanocortin 2 Receptor in the mouse Y1 cell line. Endocrinology 149:1935-41.

  • Chung TT, Webb TR, Chan LF, Cooray SN, Metherell LA, King PJ, Chapple JP and Clark AJL (2008) The majority of ACTH receptor mutations found in Familial Glucocorticoid Deficiency type 1 lead to defective trafficking of the receptor to the cell surface. Journal of Clinical Endocrinology and Metabolism 93:4948-4954.

  • Webb TR, Chan L, Cooray SN, Cheetham ME, Chapple JP and Clark AJL. (2009) Distinct MRAP domains are required for MC2R interaction and promotion of receptor trafficking. Endocrinology 150:720-6.

  • Chan LF, Webb TR, Chung T-T, Meimaridou E, Cooray SN, Guasti L, Chapple JP, , Egertová M, Elphick MR, Cheetham ME, Metherell LA and Clark AJL. (2009) MRAP and MRAP2 are bidirectional regulators of the Melanocortin receptor family.

  • Chan LF, Webb TR, Chung T-T, Meimaridou E, Cooray SN, Guasti L, Chapple JP, , Egertová M, Elphick MR, Cheetham ME, Metherell LA and Clark AJL. (2009) MRAP and MRAP2 are bidirectional regulators of the Melanocortin receptor family. Proceedings of the National Academy of Sciences USA 106: 6146-51.

  • Metherell LA, Naville D, Halaby G, Begeot M, Huebner A, Nürnberg G, Nürnberg P, Green J, Tomlinson JW, Krone NP, Lin L, Racine M, Berney DM, Achermann JC, Arlt W, Clark AJL. (2009) Nonclassic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency. Journal of Clinical Endocrinology & Metabolism. 94:3865-71.

  • Storr HL, Kind B, Parfitt DA, Chapple JP, Lorenz M, Koehler K, Huebner A, Clark AJL. (2009) Deficiency of ferritin heavy-chain nuclear import in triple a syndrome implies nuclear oxidative damage as the primary disease mechanism. Molecular Endocrinology. 23:2086-94.
  • David A, Srirangalingam U, Metherell LA, Khoo B & Clark AJL. (2010) Repair of aberrant splicing in Growth Hormone receptor by antisense oligonucleotides targeting the splice sites of a pseudoexon. Journal of Clinical Endocrinology & Metabolism 95: 3542 – 3546.

  • Cooray SN, Chung TT, Mazhar K, Szidonya L, Clark AJL.  (2011) Bioluminescence Resonance Energy Transfer reveals the Adrenocorticotropin (ACTH)-induced conformational change of the activated ACTH receptor complex in living cells. Endocrinology 152: 495 - 502.

 

 

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Professor Adrian Clark
 

Senior Staff:

Laboratory Manager:

  • Thomas Milligan

Research Staff:

  • Dr L.Chan,
  • Dr G Altobelli
  • Dr I. Bogdarina
  • Dr T T Chung
  • Dr R Gorrigan
  • Dr C Hughes

 

 

 

RAP (red) is required for trafficking of MC2R (green). Only the cell with MRAP (lower left) traffics MC2R to cell surface.

 

Antiparallel topology of the MRAP dimer. This structure appears to be unique in biology

 

 

 

 

 

 
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