Mitogen-Activated Protein Kinase: Conservation of a Three-Kinase Module From Yeast to Human

Abstract

Mitogen-activated protein kinases (MAPK) are serine-threonine protein kinases that are activated by diverse stimuli ranging from cytokines, growth factors, neurotransmitters, hormones, cellular stress, and cell adherence. Mitogen-activated protein kinases are expressed in all eukaryotic cells. The basic assembly of MAPK pathways is a three-component module conserved from yeast to humans. The MAPK module includes three kinases that establish a sequential activation pathway comprising a MAPK kinase kinase (MKKK), MAPK kinase (MKK), and MAPK. Currently, there have been 14 MKKK, 7 MKK, and 12 MAPK identified in mammalian cells. The mammalian MAPK can be subdivided into five families: MAPKerk1/2, MAPKp38, MAPKjnk, MAPKerk3/4, and MAPKerk5. Each MAPK family has distinct biological functions. In Saccharomyces cerevisiae, there are five MAPK pathways involved in mating, cell wall remodelling, nutrient deprivation, and responses to stress stimuli such as osmolarity changes. Component members of the yeast pathways have conserved counterparts in mammalian cells. The number of different MKKK in MAPK modules allows for the diversity of inputs capable of activating MAPK pathways. In this review, we define all known MAPK module kinases from yeast to humans, what is known about their regulation, defined MAPK substrates, and the function of MAPK in cell physiology.

From receptors to stress-activated MAP kinases

“…In the JNK subgroup, three genes (jnk1, jnk2 and jnk3) and ten di erent splicing variants have been described (Gupta et al, 1996;Widmann et al, 1999). JNKs are activated by two distinct MAPKKs, MKK4/SEK1 (Sanchez et al, 1994;Derijard et al, 1995), and MKK7 Yao et al, 1997;Wu et al, 1997;Tournier et al, 1997;Holland et al, 1997), in the JNK signaling unit.…”

“…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.…”

“…There are no known MAPKKKs which activate only p38s or p38s and the ERKs pathways. In addition, genetic evidence from yeast and¯ies suggests that a group of kinases which appear to function upstream of MAPKKKs may exist in certain MAPK modules (Widmann et al, 1999;Kyriakis, 1999), despite the lack of direct biochemical evidence that these kinases activate MAPKKK by phosphorylation. Thus, at least 14 di erent but structurally related kinases in this group are suggested to function as mammalian MAPKKKKs, including PAK1, 2, 3 and 4 (Manser et al, 1994;Knaus et al, 1995;Abo, 1998), GCK (Katz et al, 1994), GCKR/KHS (Shi and Kehrl, 1997;Tung and Blenis, 1997), GLK , HPK1 (Kiefer et al, 1996;Hu et al, 1996), NIK (Nck-interacting kinase)/HGK (Su et al 1997;Yao et al 1999), SOK1 (previously called UK-1; Pombo et al, 1996), Krs-1 (Taylor et al, 1996), MST1/Krs-2(Creasy and Cherno , 1995; Taylor et al, 1996), MST3 (Schinkmann and Blenis, 1997) and LOK (Kuramochi et al, 1997).…”

“…The MAP kinase signaling cascade is evolutionarily well conserved in cells from those of yeasts to humans and is typically composed of three hierarchical protein kinases including MAP kinase (MAPK), MAPK kinase (MAPKK) and MAPKK kinase (MAPKKK) (Errede and Levin, 1993;Davis, 1994;Waskiewicz and Cooper, 1995;Kyriakis and Avruch, 1996;Widmann et al, 1999;Schae er and Weber, 1999). MAPKKK phosphorylates and thereby activates MAPKK, and activated MAPKK in turn phosphorylates and activates MAPK.…”

“…In mammalian systems, at least six independent MAPK signaling units appear to function (Widmann et al, 1999;Schae er and Weber, 1999); among them, the biochemical properties of three MAPKs, the extracellular signal-regulated kinases (ERKs), the c-Jun amino-terminal kinases (JNKs; also referred to as stress-activated protein kinases or SAPKs) and the p38 MAPKs (p38s), have been characterized in some detail. Unlike the ERK signaling pathway, the JNK and p38 pathways are not preferentially activated by mitogens but by in¯ammatory cytokines such as TNF and IL-1b and a diverse array of cellular stresses including UV light, X-rays, hydrogen peroxide (H 2 O 2 ), heat and osmotic shock, and withdrawal of growth factors.…”