The mitogen-activated protein kinase (MAPK) pathway is a conserved eukaryotic signaling module that converts receptor signals into various outputs. MAPK is activated through phosphorylation by MAPK kinase (MAPKK), which is first activated by MAPKK kinase (MAPKKK). A genetic selection based on a MAPK pathway in yeast was used to identify a mouse protein kinase (TAK1) distinct from other members of the MAPKKK family. TAK1 was shown to participate in regulation of transcription by transforming growth factor-beta (TGF-beta). Furthermore, kinase activity of TAK1 was stimulated in response to TGF-beta and bone morphogenetic protein. These results suggest that TAK1 functions as a mediator in the signaling pathway of TGF-beta superfamily members.

The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor (HGF) is important for cell growth, survival, and motility and is functionally linked to the signaling pathway of VEGF, which is widely recognized as a key effector in angiogenesis and cancer progression. Dysregulation of the MET/VEGF axis is found in a number of human malignancies and has been associated with tumorigenesis. Cabozantinib (XL184) is a small-molecule kinase inhibitor with potent activity toward MET and VEGF receptor 2 (VEGFR2), as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology, including RET, KIT, AXL, and FLT3. Treatment with cabozantinib inhibited MET and VEGFR2 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro. In mouse models, cabozantinib dramatically altered tumor pathology, resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose-dependent inhibition of tumor growth in breast, lung, and glioma tumor models. Importantly, treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis, which has been observed with inhibitors of VEGF signaling that do not target MET. Collectively, these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling.

The TAK1 MAPKKK mediates activation of JNK and NF-KB in the IL-1-activated signaling pathway. Here we report the identification of TAB2, a novel intermediate in the IL-1 pathway that functionally links TAK1 to TRAF6. Expression of TAB2 induces JNK and NF-kappaB activation, whereas a dominant-negative mutant TAB2 impairs their activation by IL-1. IL-1 stimulates translocation of TAB2 from the membrane to the cytosol where it mediates the IL-1-dependent association of TAK1 with TRAF6. These results define TAB2 as an adaptor linking TAK1 and TRAF6 and as a mediator of TAK1 activation in the IL-1 signaling pathway.

Transforming growth factor-beta (TGF-beta) regulates many aspects of cellular function. A member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family, TAK1, was previously identified as a mediator in the signaling pathway of TGF-beta superfamily members. The yeast two-hybrid system has now revealed two human proteins, termed TAB1 and TAB2 (for TAK1 binding protein), that interact with TAK1. TAB1 and TAK1 were co-immunoprecipitated from mammalian cells. Overproduction of TAB1 enhanced activity of the plasminogen activator inhibitor 1 gene promoter, which is regulated by TGF-beta, and increased the kinase activity of TAK1. TAB1 may function as an activator of the TAK1 MAPKKK in TGF-beta signal transduction.

These kinases are highly Palo Alto, California 94304 related in sequence, are rapidly activated following treatment with TNF or IL-1, and specifically phosphorylate the two critical serines of IB. In addition, catalyti-Summary cally inactive forms of IKK-␣ and IKK-␤ inhibit NF-B activation mediated by TNF and IL-1, suggesting that IB kinase-␣ and -␤ (IKK-␣ and IKK-␤), the catalytic IKK-␣ and -␤ are responsible for IB phosphorylation subunits of the IKK complex, phosphorylate IB proand subsequent NF-B activation. Recently, a third teins on specific serine residues, thus targeting IB component of the IKK complex, designated NEMO/ for degradation and activating the transcription factor IKK-␥, was identified by complementation cloning in NF-NF-B. To elucidate the in vivo function of IKK-␤, we B-unresponsive cells (Yamaoka et al., 1998) and by generated IKK-␤-deficient mice. The homozygous affinity purification using antibodies to IKK-␣ (Rothwarf mouse embryo dies at ‫5.41ف‬ days of gestation due et al., 1998). NEMO is a 47 kDa protein that interacts to liver degeneration and apoptosis. IKK-␤-deficient with IKK-␣ and IKK-␤. NEMO-deficient cells are unable embryonic fibroblasts have both reduced basal NF-B to activate NF-B in response to TNF, IL-1, or LPS. activity and impaired cytokine-induced NF-B activa-Furthermore, IKK complexes lacking NEMO cannot be tion. Similarly, basal and cytokine-inducible kinase acactivated to phosphorylate IB, indicating that NEMO tivities of the IKK complex are greatly reduced in IKKis an essential component of the IKK complex. ␤-deficient cells. These results indicate that IKK-␤ is NF-B-inducing kinase (NIK) and MEKK1 have been crucial for liver development and regulation of NF-B proposed to be upstream activators of IKKs (Malinin et activity and that IKK-␣ can only partially compensate al., 1997; Nemoto et al., 1998). NIK is a MEKK family for the loss of IKK-␤. member that binds to and activates both IKK-␣ and IKK-␤ when overexpressed (Regnier et al., 1997; Woronicz et al., 1997). In addition, NIK can phosphorylate