Receptor tyrosine kinase genes were sequenced in nonsmall cell lung cancer (NSCLC) and matched normal tissue. Somatic mutations of the epidermal growth factor receptor gene EGFR were found in 15 of 58 unselected tumors from Japan and 1 of 61 from the United States. Treatment with the EGFR kinase inhibitor gefitinib (Iressa) causes tumor regression in some patients with NSCLC, more frequently in Japan. EGFR mutations were found in additional lung cancer samples from U.S. patients who responded to gefitinib therapy and in a lung adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib, but not in gefitinibinsensitive tumors or cell lines. These results suggest that EGFR mutations may predict sensitivity to gefitinib. Protein kinase activation by somatic mutation or

https://science.sciencemag.org/content/sci/early/2004/04/29/science.1099314.full.pdf

EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.

Cell signaling by receptor-tyrosine kinases

Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.

/pdf/microenvironmental-regulation-of-tumor-progression-and-4528oymlw6.pdf

Microenvironmental regulation of tumor progression and metastasis.

https://www.cell.com/cell/pdf/S0092-8674(03)00432-X.pdf

Mechanisms of TGF-β Signaling from Cell Membrane to the Nucleus

Transforming growth factor-beta (TGF-beta) proteins regulate cell function, and have key roles in development and carcinogenesis The intracellular effectors of TGF-beta signalling, the Smad proteins, are activated by receptors and translocate into the nucleus, where they regulate transcription Although this pathway is inherently simple, combinatorial interactions in the heteromeric receptor and Smad complexes, receptor-interacting and Smad-interacting proteins, and cooperation with sequence-specific transcription factors allow substantial versatility and diversification of TGF-beta family responses Other signalling pathways further regulate Smad activation and function In addition, TGF-beta receptors activate Smad-independent pathways that not only regulate Smad signalling, but also allow Smad-independent TGF-beta responses

Smad-dependent and Smad-independent pathways in TGF-beta family signalling.

https://www.cell.com/cell/pdf/S0092-8674(02)00741-9.pdf

The Conformational Plasticity of Protein Kinases

The protein Hck is a member of the Src family of non-receptor tyrosine kinases which is preferentially expressed in haematopoietic cells of the myeloid and B-lymphoid lineages. Src kinases are inhibited by tyrosine-phosphorylation at a carboxy-terminal site. The SH2 domains of these enzymes play an essential role in this regulation by binding to the tyrosine-phosphorylated tail. The crystal structure of the downregulated form of Hck has been determined and reveals that the SH2 domain regulates enzymatic activity indirectly; intramolecular interactions between the SH3 and catalytic domains appear to stabilize an inactive form of the kinase. Here we compare the roles of the SH2 and SH3 domains in modulating the activity of Hck in an investigation of the C-terminally phosphorylated form of the enzyme. We show that addition of the HIV-1 Nef protein, which is a high-affinity ligand for the Hck SH3 domain, to either the downregulated or activated form of Hck causes a large increase in Hck catalytic activity. The intact SH3-binding motif in Nef is crucial for Hck activation. Our results indicate that binding of the Hck SH3 domain by Nef causes a more marked activation of the enzyme than does binding of the SH2 domain, suggesting a new mechanism for regulation of the activity of tyrosine kinases.

Activation of the Src-family tyrosine kinase Hck by SH3 domain displacement

Crystal Structure of the Cytoplasmic Domain of the Type I TGF β Receptor in Complex with FKBP12

Activated T helper cells produce many cytokines, some of which are secreted through the immunological synapse toward the antigen-presenting cell. Here we have used immunocytochemistry, live-cell imaging and a surface-mediated secretion assay to show that there are two cytokine export pathways in T helper cells. Some cytokines, including interleukin 2 and interferon-γ, were secreted into the synapse, whereas others, including tumor necrosis factor and the chemokine CCL3 (MIP-1α), were released multidirectionally. Each secretion pathway was associated with different trafficking proteins, indicating that they are molecularly distinct processes. These data suggest that T helper cells release some cytokines into the immunological synapse to impart specific communication and others multidirectionally to promote inflammation and to establish chemokine gradients.

Morgan Huse

Papers

The Conformational Plasticity of Protein Kinases

Activation of the Src-family tyrosine kinase Hck by SH3 domain displacement

Crystal Structure of the Cytoplasmic Domain of the Type I TGF β Receptor in Complex with FKBP12

T cells use two directionally distinct pathways for cytokine secretion.

The TGF beta receptor activation process: an inhibitor- to substrate-binding switch.