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PMID:22073305

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Citation

Ye, S, Fowler, TW, Pavlos, NJ, Ng, PY, Liang, K, Feng, Y, Zheng, M, Kurten, R, Manolagas, SC and Zhao, H (2011) LIS1 regulates osteoclast formation and function through its interactions with dynein/dynactin and Plekhm1. PLoS ONE 6:e27285

Abstract

Microtubule organization and lysosomal secretion are both critical for the activation and function of osteoclasts, highly specialized polykaryons that are responsible for bone resorption and skeletal homeostasis. Here, we have identified a novel interaction between microtubule regulator LIS1 and Plekhm1, a lysosome-associated protein implicated in osteoclast secretion. Decreasing LIS1 expression by shRNA dramatically attenuated osteoclast formation and function, as shown by a decreased number of mature osteoclasts differentiated from bone marrow macrophages, diminished resorption pits formation, and reduced level of CTx-I, a bone resorption marker. The ablated osteoclast formation in LIS1-depleted macrophages was associated with a significant decrease in macrophage proliferation, osteoclast survival and differentiation, which were caused by reduced activation of ERK and AKT by M-CSF, prolonged RANKL-induced JNK activation and declined expression of NFAT-c1, a master transcription factor of osteoclast differentiation. Consistent with its critical role in microtubule organization and dynein function in other cell types, we found that LIS1 binds to and colocalizes with dynein in osteoclasts. Loss of LIS1 led to disorganized microtubules and aberrant dynein function. More importantly, the depletion of LIS1 in osteoclasts inhibited the secretion of Cathepsin K, a crucial lysosomal hydrolase for bone degradation, and reduced the motility of osteoclast precursors. These results indicate that LIS1 is a previously unrecognized regulator of osteoclast formation, microtubule organization, and lysosomal secretion by virtue of its ability to modulate dynein function and Plekhm1.

Links

PubMed PMC3207863 Online version:10.1371/journal.pone.0027285

Keywords

1-Alkyl-2-acetylglycerophosphocholine Esterase/metabolism; 1-Alkyl-2-acetylglycerophosphocholine Esterase/physiology; Animals; Cathepsin K/secretion; Cell Differentiation; Cell Survival; Dyneins/metabolism; Mice; Microtubule-Associated Proteins/metabolism; Microtubule-Associated Proteins/physiology; Osteoclasts/cytology; Protein Binding; Vesicular Transport Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:DCTN1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P63005

F

Seeded From UniProt

complete

MOUSE:TNF11

acts_upstream_of_or_within

GO:0046330: positive regulation of JNK cascade

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:109520

P

  • regulates_o_occurs_in:(CL:0000092)

Seeded From UniProt

complete

MOUSE:DC1I1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P63005

F

  • occurs_in:(CL:0000092)

Seeded From UniProt

complete

MOUSE:LIS1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:O08788
PR:O88485
PR:Q7TSI1

F

Seeded From UniProt

complete

MOUSE:LIS1

acts_upstream_of_or_within

GO:0001667: ameboidal-type cell migration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • results_in_movement_of:(CL:0000092)

Seeded From UniProt

complete

MOUSE:LIS1

acts_upstream_of_or_within

GO:0000226: microtubule cytoskeleton organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0000091)

Seeded From UniProt

complete

MOUSE:LIS1

acts_upstream_of_or_within

GO:0009306: protein secretion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0000092)

Seeded From UniProt

complete

MOUSE:LIS1

acts_upstream_of_or_within

GO:0046329: negative regulation of JNK cascade

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1100089

P

  • regulates_o_occurs_in:(CL:0000092)

Seeded From UniProt

complete

MOUSE:LIS1

acts_upstream_of_or_within

GO:0036035: osteoclast development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • results_in_development_of:(CL:0000092)

Seeded From UniProt

complete

MOUSE:PKHM1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P63005

F

Seeded From UniProt

complete

MOUSE:LIS1

acts_upstream_of_or_within

GO:0036035: osteoclast development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

results_in_development_of:(CL:0000092)

Seeded From UniProt

complete

MOUSE:LIS1

acts_upstream_of_or_within

GO:0000226: microtubule cytoskeleton organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(CL:0000091)

Seeded From UniProt

complete

MOUSE:LIS1

acts_upstream_of_or_within

GO:0001667: ameboidal-type cell migration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

results_in_movement_of:(CL:0000092)

Seeded From UniProt

complete

MOUSE:LIS1

acts_upstream_of_or_within

GO:0001961: positive regulation of cytokine-mediated signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LIS1

acts_upstream_of_or_within

GO:0046329: negative regulation of JNK cascade

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1100089

P

regulates_o_occurs_in:(CL:0000092)

Seeded From UniProt

complete

MOUSE:LIS1

acts_upstream_of_or_within

GO:0009306: protein secretion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_in:(CL:0000092)

Seeded From UniProt

complete


See also

References

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