**********************************************
* EGF-like domain cysteine pattern signature *
**********************************************

A sequence of  about thirty  to forty amino-acid  residues  long found in  the
sequence of epidermal  growth factor (EGF)  has  been shown [1,2,3,4,5]  to be
present, in   a  more or  less conserved  form, in  a  large  number  of other
proteins.  The  proteins  currently  known to contain one or more copies of an
EGF-like pattern  are  listed  below  (references are  only provided  for very
recently sequenced proteins).

 - Transforming growth factor alpha (TGF-alpha).
 - Amphiregulin, a growth factor.
 - Schwannoma-derived growth factor (SDGF).
 - Betacellulin, a growth factor [6].
 - Growth factor related proteins from  Vaccinia, Myxoma,  and  Shope  fibroma
   viruses.
 - Coagulation factors VII, IX, X (once) and XII (twice).
 - Coagulation associated proteins C, S and Z (once).
 - Urokinase and tissue plasminogen activator (TPA) (once).
 - Complement components C6, C7, C8 alpha and beta chains, and C9 (once).
 - Fibronectin (twice).
 - Laminin subunits A (15 times), B1 (13 times) and B2 (12 times).
 - Tenascin, an extracellular matrix protein (14 times).
 - Nidogen (also called entactin), a basement membrane protein (once).
 - Agrin, a basal lamina protein  that causes the aggregation of acetylcholine
   receptors on cultured muscle fibers (4 times).
 - Aggrecan (once) and versican (twice), two large proteoglycans.
 - Selectins, cell  adhesion  proteins such  as  ELAM-1 (E-selectin),  GMP-140
   (P-selectin), or the lymph-node homing receptor (L-selectin) (once).
 - Transforming growth factor beta-1 binding protein (TGF-B1-BP) (16 times).
 - Drosophila neurogenic proteins: Notch (36 times), Delta (9 times), and Slit
   (7 times).
 - Drosophila epithelial development protein Crumbs (30 times).
 - Drosophila ectodermal development protein Serrate (14 times).
 - Caenorhabditis elegans  developmental proteins lin-12 (13 times)  and glp-1
   (10 times).
 - Sea urchin protein uEGF-1 (at least 9 times).
 - Human teratocarcinoma-derived  growth factor 1  (TDGF-1)  (CRIPTO  protein)
   (once).
 - Milk fat globule-EGF factor 8 (MFG-E8) (twice).
 - Tyrosine-protein kinase receptors tek and tie (3 times) [7].

The functional  significance  of  EGF  domains  in what appear to be unrelated
proteins is not yet clear. However, a common feature is that these repeats are
found in the extracellular  domain  of membrane-bound  proteins or in proteins
known to be secreted. The EGF domain includes six cysteine residues which have
been shown (in EGF) to be  involved  in  disulfide bonds.        The schematic
representation of the EGF-like type A domain is shown here:

                        +-----------+ +--------+
                        |           | |        |
                xxxCxxxxCxxxxxCxxxxxCxCxxxxxxxxCxxx
                   |          |     ************
                   +----------+

'C': conserved cysteine involved in a disulfide bond.
'*': position of the pattern.

We have  used the region which includes the last three cysteines of the domain
as a consensus pattern.

-Consensus pattern: C-x-C-x(5)-G-x(2)-C
                    [The three C's are involved in disulfide bonds]
-Sequences known to belong to this class detected by the pattern: ALL.
-Other sequence(s) detected in SWISS-PROT: 38 other proteins. It is also found
 twice in the beta chain of the integrin family of proteins.   The presence of
 cysteine-rich repeat patterns  in  these proteins had  already been noted but
 they were said to be dissimilar with the EGF pattern [8].

-Note: the residue in position -2 to the glycine is very often an aromatic (F,
 Y or W) residue.
-Note: this pattern does not detect some  of the repeats of laminins A, B1 and
 B2, Crumbs, Notch, TGF-B1-BP, and lin-12.

-Last update: June 1994 / Text revised.

[ 1] Davis C.G.
     New Biol. 2:410-419(1990).
[ 2] Blomquist M.C., Hunt L.T., Barker W.C.
     Proc. Natl. Acad. Sci. U.S.A. 81:7363-7367(1984).
[ 3] Barker W.C., Johnson G.C., Hunt L.T., George D.G.
     Protein Nucl. Acid Enz. 29:54-68(1986).
[ 4] Doolittle R.F., Feng D.F., Johnson M.S.
     Nature 307:558-560(1984).
[ 5] Appella E., Weber I.T., Blasi F.
     FEBS Lett. 231:1-4(1988).
[ 6] Shing Y.W., Christofori G., Hanahan D., Ono Y., Sasada R., Igarashi K.,
     Folkman J.
     Science 259:1604-1607(1993).
[ 7] Ziegler S.F., Bird T.A., Schneringer J.A., Schooley K.A., Baum P.R.
     Oncogene 8:663-670(1993).
[ 8] Tamkun J.W., DeSimone D.W., Fonda D., Patel R.S., Buck C., Horwitz A.F.,
     Hynes R.O.
     Cell 46:271-282(1986).