CHAPTER 5 Growth Factors, Receptors, and Cancer The human EGF receptor (HER) signaling network.

Normal metazoan ( 後生動物 ) cells control each other’s lives Maintenance of tissue architecture.

Storage of PDGF by platelets Effects of growth factors on cells.

The Src protein functions as a tyrosine kinase

Actions of protein kinases Substrate specificity of the Src kinase

The EGF receptor functions as a tyrosine kinase

Structure of tyrosine kinase receptors

An altered growth factor receptor can function as an oncoprotein

Deregulation of receptor firing

A growth factor gene can become an oncogene: the case of sis

Transphosphorylation underlies the operations of receptor tyrosine kinases Formation of phosphotyrosine on the EGFR following ligand addition Apparent autophosphorylation of EGFR 32 PO 4

Receptor dimerization, ligand binding, transphosphorylation and glioblastoma pathogenesis

Alternative mechanisms of growth factor-induced receptor dimerization. homodimer triple Back-to-back

Gene fusion causing constitutively dimerized receptors

Multiple structural alterations affect Kit receptor firing. GIST: gastrointestinal stromal tumor AML: acute myelogenous leukemia Kit receptor

Yet other types of receptors enable mammalian cells to communicate with their environment Structure of cytokine receptors. Structure of the TGF-  receptor Jaks (Janus kinases) Noncovalently attached

Structure of the Notch receptor Two successive proteolytic cleavages

The Patched-Smoothened signaling system Trapping Gli

Canonical Wnt signaling via Frizzled receptors

Non-canonical Wnt signaling via Frizzled receptors

Nuclear receptors sense the presence of low–molecular– weight lipophilic ligands Steroid sex hormones, retinoids, vitamin D Estrogen, progesterone and androgen RXR (retinoid X receptor) PPAR-  (peroxisome proliferator-activated receptor-  ) DES (E2 mimic diethylstibestrol) Co-activators Co-repressors

Extracellular matrix Glycoprotein, hyaluronan and proteoglycans

Integrin receptors sense association between the cell and the extracellular matrix Mg 2+, Mn 2+, Ca 2+  2  1 integrin- collagen I

Integrin tethering to the ECM and cytoskeleton Focal adhersion Actin fiber Intermediary protein

Some integrins are essential for tumorigenesis

The Ras protein, an apparent component of the downstream signaling cascade, functions as a G protein

The structure of the Ras protein and its response to GTP binding.

Alternative mechanisms of transformation by Ras. 5 min after EGF is added