Identification of a Frizzled-like cysteine rich domain in the extracellular region of developmental receptor tyrosine kinases.
In Drosophila, members of the Frizzled family of tissue-polarity genes encode proteins that appear to function as cell-surface receptors for Wnts. The Frizzled genes belong to the seven transmembrane class of receptors (7TMR) and have on their extracellular region a cysteine-rich domain that has been implicated as the Wnt binding domain. This region has a characteristic spacing of ten cysteines, which has also been identified in FrzB (a secreted antagonist of Wnt signaling) and Smoothened (another 7TMR, which is involved in suppression of the hedgehog pathway). We have identified, using BLAST, sequence similarity between the cysteine-rich domain of Frizzled and several receptor tyrosine kinases, which have roles in development. These include the muscle-specific receptor tyrosine kinase (MuSK), the neuronal specific kinase (NSK2), and ROR1 and ROR2. At present, the ligands for these developmental tyrosine kinases are unknown. Our results suggest that Wnt-like ligands may bind to these developmental tyrosine kinases.
Division of Mathematical Biology, National Institute for Medical Research, London, United Kingdom.
J
J
Saldanha
J
J
Singh
D
D
Mahadevan
D000595:Amino Acid Sequence; D000818:Animals; D003545:Cysteine; D016208:Databases, Factual; D029721:Drosophila Proteins; D004331:Drosophila melanogaster; D051157:Frizzled Receptors; D018398:Homeodomain Proteins; D007301:Insect Hormones / Q000737:chemistry; D008565:Membrane Proteins / Q000737:chemistry*; D008969:Molecular Sequence Data; D005810:Multigene Family; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry* / Q000145:classification; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000145:classification; D011950:Receptors, Cholinergic; D043562:Receptors, G-Protein-Coupled; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D051153:Wnt Proteins; D029961:Zebrafish Proteins / Q000737:chemistry* / Q000145:classification
D029721:Drosophila Proteins; D051157:Frizzled Receptors; D018398:Homeodomain Proteins; D007301:Insect Hormones; D008565:Membrane Proteins; C490829:MuSK protein, zebrafish; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D011950:Receptors, Cholinergic; D043562:Receptors, G-Protein-Coupled; D051153:Wnt Proteins; D029961:Zebrafish Proteins; C058784:fz protein, Drosophila; C095714:MUSK protein, human; C114861:NSK2 protein, Drosophila; C078716:ROR1 protein, human; C078717:ROR2 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D057050:Receptor Tyrosine Kinase-like Orphan Receptors; D003545:Cysteine