Sprouty: how does the branch manager work?
Since the discovery of the prototypical Sprouty (Spry) protein in Drosophila, there has been an effort to determine how these novel modulators of the Ras/MAP-kinase pathway function. A clue to their mechanism of action comes from the several highly conserved sequences within all the currently known Spry isoforms: an approximately 110-residue cysteine-rich sequence in the C-terminal half that directs Spry proteins to a concentration of signaling proteins at the plasma membrane; a small motif surrounding a tyrosine residue (Y55 in human Spry2) that is responsible for interaction with other proteins. In cultured mammalian cells, hSpry2 inhibits epidermal growth factor receptor (EGFR) endocytosis and subsequently sustains the activation of MAP kinase but negatively regulates the same pathway following stimulation of fibroblast growth factor receptors (FGFRs). Current evidence indicates that Cbl is a key protein that interacts directly with Spry2 following activation of receptor tyrosine kinases (RTKs). It appears to be the ability of Cbl to interact as an E3 ubiquitin ligase on specific target proteins and as a docking protein in other contexts that dictates the differential effects Spry2 has on the Ras/MAP-kinase pathway following EGFR and FGFR activation.
Guy
Graeme R
GR
Signal Transduction Laboratory, Institute of Molecular and Cell Biology, 30 Medical Drive, Singapore 117 609, Republic of Singapore. mcbgg@imcb.nus.edu.sg
Wong
Esther S M
ES
Yusoff
Permeen
P
Chandramouli
Sumana
S
Lo
Ting Ling
TL
Lim
Jormay
J
Fong
Chee Wai
CW
D000595:Amino Acid Sequence; D000818:Animals; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D018631:ras Proteins / Q000378:metabolism*
D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D011506:Proteins; C486055:SPRY1 protein, human; C485561:SPRY2 protein, human; C407225:SPRY3 protein, human; C499038:SPRY4 protein, human; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins