SH2 and SH3 domains: potential targets for anti-cancer drug design.

Protein-tyrosine kinases interact with a diverse group of signaling molecules that share common structural elements known as Src homology 2 and 3 (SH2 and SH3) domains. SH2 domains bind with high affinity to peptide sequences within target proteins that contain phosphorylated tyrosine residues, but have no affinity for the unphosphorylated sequence. This property allows activated tyrosine kinases to initiate signal transduction by recruiting downstream effectors with SH2 domains. SH3 domains also mediate protein-protein interaction. Target sequences for SH3 domains are rich in proline and hydrophobic amino acids, but do not require phosphorylation. SH2- and SH3-mediated protein-protein interactions are required for the transmission of proliferative signals initiated by tyrosine kinases (e.g., Ras activation or stimulation of phosphatidylinositol-3' kinase activity). Peptidomimetic ligands based on the sequence of target proteins for SH2 and SH3 domains may represent new lead compounds for the therapy of proliferative diseases that are dependent upon constitutively activated tyrosine kinases (e.g., BCR/ABL in chronic myelogenous and acute lymphocytic leukemias or HER-2/Neu in breast and ovarian cancer.

[1]  S. Shoelson,et al.  Nonhydrolyzable phosphotyrosyl mimetics for the preparation of phosphatase-resistant SH2 domain inhibitors. , 1994, Biochemistry.

[2]  M. Moran,et al.  Protein-tyrosine kinases regulate the phosphorylation, protein interactions, subcellular distribution, and activity of p21ras GTPase-activating protein , 1991, Molecular and cellular biology.

[3]  I. Campbell,et al.  The GTPase dynamin binds to and is activated by a subset of SH3 domains , 1993, Cell.

[4]  J. Wang,et al.  Abl tyrosine kinase in signal transduction and cell-cycle regulation. , 1993, Current opinion in genetics & development.

[5]  P Cicchetti,et al.  Identification of a ten-amino acid proline-rich SH3 binding site. , 1993, Science.

[6]  J. Troppmair,et al.  The ins and outs of Raf kinases. , 1994, Trends in biochemical sciences.

[7]  Hongtao Yu,et al.  Structural basis for the binding of proline-rich peptides to SH3 domains , 1994, Cell.

[8]  M. Nakafuku,et al.  Function of Ras as a molecular switch in signal transduction. , 1992, The Journal of biological chemistry.

[9]  J. Bolen,et al.  The Src family of tyrosine protein kinases in hemopoietic signal transduction , 1992, Stem cells.

[10]  T. Pawson,et al.  The N‐terminal region of GAP regulates cytoskeletal structure and cell adhesion. , 1993, The EMBO journal.

[11]  M. White,et al.  Regulation of Phosphatidylinositol 3′-Kinase by Tyrosyl Phosphoproteins , 1995, The Journal of Biological Chemistry.

[12]  W Godolphin,et al.  Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. , 1989, Science.

[13]  O. Silvennoinen,et al.  Signaling by the cytokine receptor superfamily: JAKs and STATs. , 1994, Trends in biochemical sciences.

[14]  K. Izuhara,et al.  Interaction of the c-fes proto-oncogene product with the interleukin-4 receptor. , 1994, The Journal of biological chemistry.

[15]  S. Shoelson,et al.  Inhibition of SH2 domain/phosphoprotein association by a nonhydrolyzable phosphonopeptide. , 1992, Biochemistry.

[16]  S. Schreiber,et al.  Biased combinatorial libraries: novel ligands for the SH3 domain of phosphatidylinositol 3-kinase , 1993 .

[17]  L. Cantley,et al.  Phosphatidylinositol-3 kinase and growth regulation. , 1992, Cold Spring Harbor symposia on quantitative biology.

[18]  S. Rhee.  Inositol phospholipid-specific phospholipase C: interaction of the γ isoform with tyrosine kinase , 1991 .

[19]  R. Jove,et al.  The Ras GTPase-activating Protein (GAP) Is an SH3 Domain-binding Protein and Substrate for the Src-related Tyrosine Kinase, Hck (*) , 1995, Journal of Biological Chemistry.

[20]  A. Sparks,et al.  Identification and characterization of Src SH3 ligands from phage-displayed random peptide libraries. , 1994, The Journal of biological chemistry.

[21]  N. Kohl,et al.  Farnesyltransferase inhibitors: Ras research yields a potential cancer therapeutic , 1994, Cell.

[22]  K. Arai,et al.  c‐fps/fes protein‐tyrosine kinase is implicated in a signaling pathway triggered by granulocyte‐macrophage colony‐stimulating factor and interleukin‐3. , 1993, The EMBO journal.

[23]  J. Kuriyan,et al.  Binding of a high affinity phosphotyrosyl peptide to the Src SH2 domain: Crystal structures of the complexed and peptide-free forms , 1993, Cell.

[24]  S. Shoelson,et al.  Cyclic peptide inhibitors of phosphatidylinositol 3-kinase p85 SH2 domain binding. , 1994, Biochemical and biophysical research communications.

[25]  A. Levitzki,et al.  Tyrosine kinase inhibition: an approach to drug development. , 1995, Science.

[26]  John Kuriyan,et al.  Structures of SH2 and SH3 domains , 1993 .

[27]  A. Kazlauskas,et al.  Phospholipase C-γ1 and phosphatidylinositol 3 kinase are the downstream mediators of the PDGF receptor's mitogenic signal , 1993, Cell.

[28]  Y. Yazaki,et al.  Erythropoietin induces tyrosine phosphorylation and kinase activity of the c-fps/fes proto-oncogene product in human erythropoietin-responsive cells. , 1993, Blood.

[29]  J. Schlessinger,et al.  Phosphatidylinositol 3-kinase p85 SH2 domain specificity defined by direct phosphopeptide/SH2 domain binding. , 1993, Biochemistry.

[30]  T. Pawson,et al.  SH2 and SH3 domains: From structure to function , 1992, Cell.

[31]  D. Baltimore,et al.  Identification of a protein that binds to the SH3 region of Abl and is similar to Bcr and GAP-rho. , 1992, Science.

[32]  Nanxin Li,et al.  Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling , 1993, Nature.

[33]  M. Jaye,et al.  Identification of a Src SH3 domain binding motif by screening a random phage display library. , 1994, The Journal of biological chemistry.

[34]  T Pawson,et al.  Specific motifs recognized by the SH2 domains of Csk, 3BP2, fps/fes, GRB-2, HCP, SHC, Syk, and Vav , 1994, Molecular and cellular biology.

[35]  J. Schlessinger,et al.  How receptor tyrosine kinases activate Ras. , 1993, Trends in biochemical sciences.

[36]  T. Pawson,et al.  Nuclear magnetic resonance structure of an SH2 domain of phospholipase C-γ1 complexed with a high affinity binding peptide , 1994, Cell.

[37]  J. Cambier,et al.  Activation of phosphatidylinositol-3' kinase by Src-family kinase SH3 binding to the p85 subunit. , 1994, Science.

[38]  W. Fantl,et al.  Signalling by receptor tyrosine kinases. , 1993, Annual review of biochemistry.

[39]  T. Pawson,et al.  SH2 domains recognize specific phosphopeptide sequences , 1993, Cell.

[40]  G. Dreyfuss,et al.  Identification of Src, Fyn, and Lyn SH3-binding proteins: implications for a function of SH3 domains , 1994, Molecular and cellular biology.

[41]  S. Schreiber,et al.  Two binding orientations for peptides to the Src SH3 domain: development of a general model for SH3-ligand interactions. , 1995, Science.

[42]  J. Gibbs,et al.  Pharmaceutical research in molecular oncology , 1994, Cell.

[43]  J. Brugge.  New intracellular targets for therapeutic drug design. , 1993, Science.

[44]  F. McCormick,et al.  Regulators and effectors of ras proteins. , 1991, Annual review of cell biology.

[45]  W. McGuire,et al.  Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. , 1987, Science.

[46]  D. Baltimore,et al.  Signalling through SH2 and SH3 domains. , 1993, Trends in cell biology.

[47]  S. Schreiber,et al.  Solution structure of the SH3 domain of Src and identification of its ligand-binding site. , 1992, Science.

[48]  C. Turck,et al.  Distinct phosphotyrosines on a growth factor receptor bind to specific molecules that mediate different signaling pathways , 1992, Cell.

[49]  J. Gibbs,et al.  src-homology 2 (SH2) domain ligation as an allosteric regulator: modulation of phosphoinositide-specific phospholipase C gamma 1 structure and activity. , 1995, Biochemical Journal.