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Molecular and Cellular Biology, September 1999, p. 6427-6440, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Functional Analysis of H-Ryk, an Atypical Member of the Receptor Tyrosine Kinase Family

R. M. Katso,1 R. B. Russell,2 and T. S. Ganesan1,*

Molecular Oncology Laboratories, Imperial Cancer Research Fund, Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS,1 and Biomolecular Modelling Laboratory, Imperial Cancer Research Fund, London WC2A 3PX,2 United Kingdom

Received 9 October 1998/Returned for modification 10 December 1998/Accepted 25 May 1999

H-Ryk is an atypical receptor tyrosine kinase which differs from other members of this family at a number of conserved residues in the activation and nucleotide binding domains. Using a chimeric receptor approach, we demonstrate that H-Ryk has impaired catalytic activity. Despite the receptor's inability to undergo autophosphorylation or phosphorylate substrates, we demonstrate that ligand stimulation of the chimeric receptor results in activation of the mitogen-activated protein kinase pathway. The ability to transduce signals is abolished by mutation of the invariant lysine (K334A) in subdomain II of H-Ryk. Further, by in vitro mutagenesis, we show that the amino acid substitutions in the activation domain of H-Ryk account for the loss of catalytic activity. In addition to the essential aspartate residue, either phenylalanine or glycine is required in the activation domain to maintain proper conformation of the catalytic domain and thus ensure receptor autophosphorylation. Homology modelling of the catalytic domain of H-Ryk provides a rationale for these findings. Thus, the signalling properties of H-Ryk are divergent from those of other classical receptor tyrosine kinases.

* Corresponding author. Mailing address: Molecular Oncology Laboratories, Imperial Cancer Research Fund, Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom. Phone: (44) 01865 222 457. Fax: (44) 01865 222 431. E-mail: ganesan{at}icrf.icnet.uk.

Molecular and Cellular Biology, September 1999, p. 6427-6440, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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