Cripto enhances the tyrosine phosphorylation of Shc and activates mitogen-activated protein kinase (MAPK) in mammary epithelial cells.
Cripto-1 (CR-1), a recently discovered protein of the epidermal growth factor (EGF) family, was found to interact with a high affinity, saturable binding site(s) on HC-11 mouse mammary epithelial cells and on several different human breast cancer cell lines. This receptor exhibits specificity for CR-1, since other EGF-related peptides including EGF, transforming growth factor alpha, heparin-binding EGF-like growth factor, amphiregulin, epiregulin, betacellulin, or heregulin beta1 that bind to either the EGF receptor or to other type 1 receptor tyrosine kinases such as erb B-3 or erb B-4 fail to compete for binding. Conversely, CR-1 was found not to directly bind to or to activate the tyrosine kinases associated with the EGFR, erb B-2, erb B-3, or erb B-4 either alone or in various pairwise combinations which have been ectopically expressed in Ba/F3 mouse pro-B lymphocyte cells. However, exogenous CR-1 could induce an increase in the tyrosine phosphorylation of 185- and 120-kDa proteins and a rapid (within 3-5 min) increase in the tyrosine phosphorylation of the SH2-containing adaptor proteins p66, p52, and p46 Shc in mouse mammary HC-11 epithelial cells and in human MDA-MB-453 and SKBr-3 breast cancer cells. CR-1 was also found to promote an increase in the association of the adaptor Grb2-guanine nucleotide exchange factor-mouse son of sevenless (mSOS) signaling complex with tyrosine-phosphorylated Shc in HC-11 cells. Finally, CR-1 was able to increase p42(erk-2) mitogen-activated protein kinase (MAPK) activity in HC-11 cells within 5-10 min of treatment. These data demonstrate that CR-1 can function through a receptor which activates intracellular components in the ras/raf/MEK/MAPK pathway.
Kannan
S
S
Tumor Growth Factor Section, Laboratory of Tumor Immunology and Biology, NIC, National Institutes of Health, Bethesda, Maryland 20892, USA.
De Santis
M
M
Lohmeyer
M
M
Riese
D J
DJ
Smith
G H
GH
Hynes
N
N
Seno
M
M
Brandt
R
R
Bianco
C
C
Persico
G
G
Kenney
N
N
Normanno
N
N
Martinez-Lacaci
I
I
Ciardiello
F
F
Stern
D F
DF
Gullick
W J
WJ
Salomon
D S
DS
D000818:Animals; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D004789:Enzyme Activation; D004815:Epidermal Growth Factor; D004848:Epithelium / Q000201:enzymology; D005260:Female; D058851:GPI-Linked Proteins; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008321:Mammary Glands, Animal / Q000201:enzymology*; D008562:Membrane Glycoproteins; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D009363:Neoplasm Proteins / Q000494:pharmacology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism*; D018909:src Homology Domains
D058851:GPI-Linked Proteins; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C070636:TDGF1 protein, human; C489450:Tdgf1 protein, mouse; D014443:Tyrosine; D004815:Epidermal Growth Factor; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1