Molecular Cloning of Mitogen-activated Protein/ERK Kinase Kinases (MEKK) 2 and 3

Potentiation of apoptosis by low dose stress stimuli in cells expressing activated MEK kinase 1

“…These ®ndings are characteristic for expression of DMEKK1; expression of other kinases such as activated Raf-1 actually enhance the growth of cells and enhance colony size in this assay (LassignalJohnson et al, 1996). We have also found that expression of the kinase domain of MEKK 2 and 3 (Blank et al, 1996) does not induce apoptosis (CW, unpublished results), indicating that the apoptotic response is a speci®c and functional consequence of DMEKK1 kinase activity and is not mimicked by other MEKKs that activate the JNK pathway.…”

“…The JNK/SAPKs, like the extracellular response kinases (ERKs; p42/p44 MAPKs), are members of a sequential protein kinase pathway (Johnson and Vaillancourt, 1994). JNK/ SAPKs are phosphorylated, resulting in their activation, by JNK kinase (JNKK/stress-activated ERK kinase or SEK-1) (Sanchez et al, 1994;Lin et al, 1995); JNKK/SEK-1 is itself regulated by phosphorylation by MEK kinases (MEKKs) (Lange-Carter et al, 1993;Blank et al, 1996;Gerwins et al, 1997). The MEKK-regulated JNK/SAPK sequential protein kinase pathway is parallel to the Raf/MEK/ERK pathway and regulated in part by GTP-binding proteins including Ras, Cdc42 and Rac (Coso et al, 1995;Minden et al, 1995;Gerwins et al, 1997).…”

From receptors to stress-activated MAP kinases

“…In contrast to MAPKs and MAPKKs, the MAPKKKs in the JNK and p38 modules are highly divergent in structure and gene number. To date, eleven di erent MAPKKKs have been identi®ed as upstream activators of JNK pathway (Widmann et al, 1999); MEKK1 (Lange et al, 1993), MEKK2 (Blank et al, 1996), MEKK3 (Blank et al, 1996), MTK1/ MEKK4 (Takekawa et al, 1997;Gerwins et al, 1997), Tpl-2/Cot (Aoki et al, 1991;Salmeron et al, 1996), MUK/DLK/ZPK Holzman et al, 1994;Reddy and Pleasure, 1994), MLK-2/MST (Dorow et al, 1995;Hirai et al, 1997), MLK-3/SPRK/ PTK-1 (Rana et al, 1996;Gallo et al, 1994;Ing et al, 1994), TAK1 (Yamaguchi et al, 1995), ASK1/ MAPKKK5 Ichijo et al, 1997) and ASK2 (Saitoh and Ichijo, unpublished observation)/MAPKKK6 (Wang et al, 1998) have been shown to activate JNKs by overexpression (Figure 1). Of these, MEKK1, MEKK2, MEKK3 and Tpl-2 can also activate the ERK pathway, while only TAK1, ASK1 and MTK1 have been shown to strongly activate p38s as well.…”

BMP-induced growth suppression in colon cancer cells is mediated by p21WAF1 stabilization and modulated by RAS/ERK

“…Activation of RAS (i.e. through EGFR stimulation) or oncogenic RAS (via mutation and constitutive activation) exerts its effects on multiple downstream effector molecules, one of which is RAF, a serine-threonine kinase that activates MEK1 and 2 kinases, which in turn activate Erk kinases 1 and 2 [8][9][10]. Once phosphorylated, ERK 1 and 2 are free to phosphorylate other cytoplasmic targets as well as translocate to the nucleus and stimulate the activity of an assortment of transcription factors.…”