2. '''Alteration of transcellular transducers/receptors'''

2. '''Alteration of transcellular transducers/receptors'''

*GF receptors often carry tyrosine kinase activities in the cytoplasmic domains

*GF receptors often carry tyrosine kinase activities in the cytoplasmic domains

*In tumor cells, the receptors are overexpressed - hyperresponsive to ambient levels of GFs (normally would not trigger proliferation)

*In tumor cells, the receptors are overexpressed - '''hyperresponsive''' to ambient levels of GFs (normally would not trigger proliferation)

**epidermal GF receptor (EGF-R/erbB) upregulated in stomach, brain, and breast tumors

**epidermal GF receptor (EGF-R/erbB) upregulated in stomach, brain, and breast tumors

**HER2/neu receptor overexpressed in stomach and mammary carcinomas

**HER2/neu receptor overexpressed in stomach and mammary carcinomas

*Overexpression >> ligand-independent signaling (can also be achieved by structural alteration of receptors)

*Overexpression >> ligand-independent signaling (can also be achieved by structural alteration of receptors)

**truncated EGF-R lacking cytoplasmic domain is activated constitutively

**truncated EGF-R lacking cytoplasmic domain is '''activated constitutively'''

*Tumor cells can switch types of extracellular matrix receptors (integrins) they express - favors those that transmit progrowth signals

*Tumor cells can '''switch types''' of extracellular matrix receptors (integrins) they express - '''favors those that transmit pro-growth signals'''

**These cell surface receptors ''physically link'' to ECM

**These cell surface receptors ''physically link'' to ECM

**Successful binding to specific moieties of ECM >> integrins transduce signals into the cell

**Successful binding to specific moieties of ECM >> integrins transduce signals into the cell

3. '''Alteration of intracellular circuits translating those signals'''

3. '''Alteration of intracellular circuits translating those signals'''

*receive that process signals transduced by the cell surface receptors

*receive that process signals transduced by the cell surface receptors

*Structurally altered forms of Ras proteins release flux of mitogenic signals into cells without stimulation by normal upstream regulators

*Structurally altered forms of Ras proteins '''release flux of mitogenic signals''' into cells '''without stimulation''' by normal upstream regulators

[[ไฟล์:Wiring.jpg]]

[[ไฟล์:Wiring.jpg]]

*The cascade is linked via cross-talking connections with other pathways - enabling signals to cause multiple cellular effects

*The cascade is linked via cross-talking connections with other pathways - enabling signals to cause '''multiple cellular effects'''

**Direct interaction of ''Ras protein'' with survival-promoting ''PI3 kinase'' >> growth signals >> survival signals within the cell

**Direct interaction of ''Ras protein'' with survival-promoting ''PI3 kinase'' >> growth signals >> survival signals within the cell