LOK Is a Novel Mouse STE20-like Protein Kinase That Is Expressed Predominantly in Lymphocytes

Abstract

We have identified a new gene, designated lok (lymphocyte-oriented kinase), that encodes a 966-amino acid protein kinase whose catalytic domain at the N terminus shows homology to that of the STE20 family members involved in mitogen-activated protein (MAP) kinase cascades. The non-catalytic domain of LOK does not have any similarity to that of other known members of the family. There is a proline-rich motif with Src homology region 3 binding potential, followed by a long coiled-coil structure at the C terminus. LOK is expressed as a 130-kDa protein, which was detected predominantly in lymphoid organs such as spleen, thymus, and bone marrow, in contrast to other mammalian members of the STE20 family. LOK phosphorylated itself as well as substrates such as myelin basic protein and histone IIA on serine and threonine residues but not on tyrosine residues, establishing LOK as a novel serine/threonine kinase. When coexpressed in COS7 cells with the known MAP kinase isoforms (ERK, JNK, and p38), LOK activated none of them in contrast to PAK-and GCK-related kinases. These results suggest that LOK could be involved in a novel signaling pathway in lymphocytes, which is distinct from the known MAP kinase cascades.

Induction of apoptosis by SLK, a Ste20-related kinase

“…Database searches revealed that the cloned cDNA encodes a protein kinase highly related to LOK, a Ste20-related protein kinase preferentially expressed in lymphocytes (Kuramochi et al, 1997). Analysis of the kinase domain shows that SLK is also related to MST1/2 (Creasy and Cherno , 1995; Katoh et al, 1995;Schinkmann and Blenis, 1997) and more distantly related to Ste20, a yeast kinase involved in the pheromone response pathway (Zhao et al, 1995).…”

“…The catalytic core extended further, up to residue 282 and presented all the characteristic subdomains of serine/threonine kinases (Hanks and Hunter, 1995) (Figure 2a). Alignments and database scans revealed that SLK displayed 74% identity, in the kinase domain, to LOK, a novel kinase preferentially expressed in lymphocytes (Kuramochi et al, 1997) (Figure 2a). The SLK kinase domain was also found to be related to MST1 and MST2, both Ste20-like kinases (Creasy and Cherno , 1995;Katoh et al, 1995;Schinkmann and Blenis, 1997).…”

Germinal center kinases in immune regulation

“…122 The GCK-V subfamily member LOK is a 130-kDa serine/threonine kinase predominantly expressed in lymphoid tissues. 123 LOK does not activate MAPK signaling but is involved in LFA-1-mediated lymphocyte adhesion. 124 SLK, which is similar to LOK, can regulate focal adhesion turnover through unknown mechanism that involves FAK.…”

From receptors to stress-activated MAP kinases

“…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). Most of the MAPKKKKs, but not SOK1, Krs-1, MST3 and LOK, can activate JNK by overexpression.…”