Phosphorylation of CLIP-170 by LRRK1 regulates EGFR trafficking by promoting recruitment of p150Glued to MT plus-ends

Kedashiro, Shin; Pastuhov, Strahil Iv.; Nishioka, Tomoki; Watanabe, Takashi; Kaibuchi, Kozo; Matsumoto, Kunihiro; Hanafusa, Hiroshi

doi:10.1242/jcs.161547

Cited by 26 publications

(29 citation statements)

References 54 publications

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“…2a). We mutated this residue to alanine and examined the kinase activity of the resulting mutant protein, LRRK1(T1400A), in an in vitro kinase assay using the carboxyterminal fragment of CLIP-170 as a substrate 28 . Kinase activity was absent in the LRRK1(T1400A) mutant, similar to the kinase-defective mutant LRRK1(K1243M) (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

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PLK1-dependent activation of LRRK1 regulates spindle orientation by phosphorylating CDK5RAP2

et al. 2015

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Correct formation of the cell division axis requires the initial precise orientation of the mitotic spindle. Proper spindle orientation depends on centrosome maturation, and Polo-like kinase 1 (PLK1) is known to play a crucial role in this process. However, the molecular mechanisms that function downstream of PLK1 are not well understood. Here we show that LRRK1 is a PLK1 substrate that is phosphorylated on Ser 1790. PLK1 phosphorylation is required for CDK1-mediated activation of LRRK1 at the centrosomes, and this in turn regulates mitotic spindle orientation by nucleating the growth of astral microtubules from the centrosomes. Interestingly, LRRK1 in turn phosphorylates CDK5RAP2(Cep215), a human homologue of Drosophila Centrosomin (Cnn), in its γ-tubulin-binding motif, thus promoting the interaction of CDK5RAP2 with γ-tubulin. LRRK1 phosphorylation of CDK5RAP2 Ser 140 is necessary for CDK5RAP2-dependent microtubule nucleation. Thus, our findings provide evidence that LRRK1 regulates mitotic spindle orientation downstream of PLK1 through CDK5RAP2-dependent centrosome maturation.

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Section: Resultsmentioning

confidence: 99%

“…Human LRRK1 is related to the familial Parkinsonism gene product Park8/LRRK2 and belongs to the ROCO family of proteins 25 . We have previously demonstrated that LRRK1 regulates the endosomal trafficking of the epidermal growth factor (EGF) receptor in interphase cells [26][27][28] . However, the role of LRRK1 during mitosis remains unknown.…”

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confidence: 99%

PLK1-dependent activation of LRRK1 regulates spindle orientation by phosphorylating CDK5RAP2

et al. 2015

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“…This promotes the association of CLIP-170 with dynein–dynactin complex formation, and the subsequent recruitment of p150 Glued to microtubule plus ends in HEK293 human kidney cells. 61,62 Although changes in EGFR activation are known to influence osteoclast formation and survival, 63 loss of Lrrk1 in the precursors did not affect osteoclast formation and maturation. Mice with complete disruption of EGFR function exhibited a remarkable decrease in tibial trabecular bone mass with abnormalities in trabecular number and thickness due to the decreases in osteoblast number and mineralization activity, and an increase in osteoclast number.…”

Section: Lrrk1 Family Numbersmentioning

confidence: 95%

Role and mechanism of action of leucine-rich repeat kinase 1 in bone

et al. 2017

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Leucine-rich repeat kinase 1 (LRRK1) plays a critical role in regulating cytoskeletal organization, osteoclast activity, and bone resorption with little effect on bone formation parameters. Deficiency of Lrrk1 in mice causes a severe osteopetrosis in the metaphysis of the long bones and vertebrae bones, which makes LRRK1 an attractive alternative drug target for the treatment of osteoporosis and other high-turnover bone diseases. This review summarizes recent advances on the functions of the Lrrk1-related family members, Lrrk1 deficiency-induced skeletal phenotypes, LRRK1 structure-function, potential biological substrates and interacting proteins, and the mechanisms of LRRK1 action in osteoclasts.

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“…LRRK1 has been proposed to regulate EGFR trafficking in endosomes [73,92] via phosphorylation of its substrate CLIP-170, a microtubule plus-end protein [98]. LRRK2 has also been linked to vesicular trafficking, but to date it appears to modulate distinct vesicular transport events related to vesicular sorting and/or the autophagy/lysosome system [46,54,73], likely mediated by protein interactions at the late endosome or the trans-Golgi network (TGN).…”

Section: The Mammalian Paralogues Lrrk1 and Lrrk2mentioning

confidence: 99%

The function of orthologues of the human Parkinson's disease gene LRRK2 across species: implications for disease modelling in preclinical research

Langston

Rudenko

Cookson

2016

Biochemical Journal

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In the period since LRRK2 (Leucine-Rich Repeat Kinase 2) was identified as a causal gene for late-onset autosomal-dominant parkinsonism, a great deal of work has been aimed at understanding whether the LRRK2 protein might be a druggable target for Parkinson’s disease (PD). As part of this effort, animal models have been developed to explore both the normal and the pathophysiological roles of LRRK2. However, LRRK2 is part of a wider family of proteins whose functions in different organisms remain poorly understood. In this review, we compare the information available on biochemical properties of LRRK2 homologues and orthologues from different species from invertebrates (e.g., Caenorhabditis elegans and Drosophila melanogaster) to mammals. We particularly discuss the mammalian LRRK2 homologue, LRRK1, and those species where there is only a single lrrk homologue, discussing examples where each of the LRRK family of proteins has distinct properties as well as those cases where there appear to be functional redundancy. We conclude that uncovering the function of LRRK2 orthologues will help elucidate the key properties of human LRRK2 as well as to improve understanding of the suitability of different animal models for investigation of LRRK2-related PD.

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Phosphorylation of CLIP-170 by LRRK1 regulates EGFR trafficking by promoting recruitment of p150Glued to MT plus-ends

Abstract: We apologise to the authors and readers for any confusion that this error might have caused.

Cited by 26 publications

References 54 publications

PLK1-dependent activation of LRRK1 regulates spindle orientation by phosphorylating CDK5RAP2

PLK1-dependent activation of LRRK1 regulates spindle orientation by phosphorylating CDK5RAP2

Role and mechanism of action of leucine-rich repeat kinase 1 in bone

The function of orthologues of the human Parkinson's disease gene LRRK2 across species: implications for disease modelling in preclinical research

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