Identification of a Novel Kinesin-related Protein, KRMP1, as a Target for Mitotic Peptidyl-prolyl Isomerase Pin1

Abstract

Mitosis utilizes a number of kinesin-related proteins (KRPs). Here we report the identification of a novel KRP termed KRMP1, which has a deduced 1780-amino acid sequence composed of ternary domains. The amino-terminal head domain is most similar to the kinesin motor domain of the MKLP-1 subfamily and has an intrinsic ATPase activity that is diminished by substituting the consensus Lys-168 with Arg. The central stalk domain is predicted to form a long ␣-helical coiled-coil, and can interact with each other in vivo. An in vivo labeling experiment revealed that KRMP1 is phosphorylated, and we also found that the region within the tail domain containing Thr-1604 as the cdc2 kinase phosphorylation site differs from the bimC box conserved in the bimC subfamily of KRPs. Immunofluorescence analysis showed that endogenous KRMP1 was localized predominantly to the cytoplasm during interphase and dispersed throughout the cell during mitosis. Consistent with this finding, overexpressed KRMP1 was detected in a complicated nuclear or cytoplasmic pattern reflecting multiple nuclear localization/export signals. Furthermore, KRMP1 interacted with the mitotic peptidylprolyl isomerase Pin1 in vivo, and an in vitro interaction was detected between the tail domain of KRMP1 and the WW domain of Pin1. Overexpression of KRMP1 caused COS-7 cells to arrest at G 2 -M, and co-expression of Pin1 reversed this effect, indicating their physiological interaction. Together, our results suggest that KRMP1 is a mitotic target regulated by Pin1 and vice versa.Eukaryotic cells have a set of nucleotide-dependent molecular motors to fulfill specific demands on their viability. Cell division is the most essential and evolved system that engages a number of dynein and kinesin-related proteins (KRPs) 1 to move mitotic spindles and chromosomes in a precise and regulated order. Most of the KRPs identified thus far have been shown to be involved in the mitotic process (reviewed in Refs.

Oncogenic Role of MPHOSPH1, a Cancer-Testis Antigen Specific to Human Bladder Cancer

“…MPHOSPH1 was previously reported to interact with mitotic peptidyl-prolyl isomerase (Pin1) protein in Homo sapiens (24). However, because the Pin1 expression was undetectable in bladder cancer cells in our microarray data and semiquantitative RT-PCR analysis (data not shown), we attempted to identify protein(s) interacting with MPHOSPH1 in bladder cancer cells.…”

The vertebrate-specific Kinesin-6, Kif20b, is required for normal cytokinesis of polarized cortical stem cells and cerebral cortex size

“…Kif20b is highly similar to its sister Kinesin-6 proteins Kif23 and Kif20a in the motor head domain, but divergent in the stalk and tail, predicting different cargo binding (Miki et al, 2005). The only proteins shown to interact with KIF20B during cytokinesis, PIN1 and PRC1, are upstream regulators (Kamimoto et al, 2001;Kanehira et al, 2007;Lee et al, 2012;Lu and Zhou, 2007). Other candidate cargos of Kif20b (Maliga et al, 2013;Sapir et al, 2013) do not have known roles in cytokinesis.…”

“…Kif20b, by contrast, is vertebrate specific, and its role in cytokinesis is less understood. Kif20b was originally cloned as a mitotic phosphoprotein called Mphosph1, MPP1 (Matsumoto-Taniura et al, 1996;Westendorf et al, 1994) or KRMP1 (Kamimoto et al, 2001). KIF20B knockdown in dividing human cell lines did not disrupt cytokinetic furrowing, but increased abscission failures (Abaza et al, 2003;Kanehira et al, 2007).…”

MPHOSPH1: A Potential Therapeutic Target for Hepatocellular Carcinoma

“…In searching for novel HCC targets that potentially increase chemotherapy efficacy, we focused on the kinesin protein MPHOSPH1, first identified through its in vivo interaction with the mitotic peptidyl-prolylisomerase PIN1 (30). In the current study, we investigated the efficacy of the combined treatment of targeting MPHOSPH1 in combination with taxol in HCC xenograft models, and demonstrated that reducing endogenous MPHOSPH1 significantly enhanced the cytotoxic effect of taxol against HCC, which suggests that MPHOSPH1 is a potential target for HCC therapy.…”