INT257665

Context Info Confidence 0.39 First Reported 2009 Last Reported 2009 Negated 0 Speculated 0 Reported most in Body Documents 1 Total Number 14 Disease Relevance 0.67 Pain Relevance 0.09

protein complex (Nphs1, Pard3) cytoplasm (Pard3) lipid binding (Pard3) cell adhesion (Nphs1) plasma membrane (Nphs1) cytoskeleton (Pard3)

Anatomy Link Frequency tail 2 podocytes 2 diaphragms 1 Nphs1 (Mus musculus) Pard3 (Mus musculus)

Pain Link Frequency Relevance Heat Kinase C 14 88.24 anesthesia 14 5.00 alcohol 14 5.00

Disease Link Frequency Relevance Heat Focal Segmental Glomerulosclerosis 84 99.52 Nephrotic Syndrome 14 73.44 Disease 70 71.44 Renal Disease 42 41.92 Adhesions 14 27.72 Death 14 5.80 Sprains And Strains 14 5.00 Proteinuria 14 5.00 Renal Failure 14 5.00

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Key:

Protein

Mutation

Event

Anatomy

Negation

Speculation

Pain term

Disease term

This suggests that PAR3 can serve as a scaffold to associate aPKC and the nephrin–podocin complex to organize slit diaphragms.

nephrin Binding (associate) of PAR3 in diaphragms

1) Confidence 0.39 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2614475 Disease Relevance 0 Pain Relevance 0

Next, we used immunoprecipitation to examine whether endogenous PAR3 forms a protein complex with nephrin and podocin.

nephrin Binding (complex) of PAR3

2) Confidence 0.39 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2614475 Disease Relevance 0 Pain Relevance 0

aPKC–PAR3 complex associates with the nephrin–podocin complex

nephrin Binding (associates) of PAR3

3) Confidence 0.39 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2614475 Disease Relevance 0 Pain Relevance 0

This indicates that the cytoplasmic tail of nephrin can bind directly to the PDZ domains of PAR3.

nephrin Binding (bind) of PAR3 in tail

4) Confidence 0.39 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2614475 Disease Relevance 0 Pain Relevance 0

To examine the region of PAR3 that is responsible for the formation of the complex with nephrin, various PAR3 mutants (Figure 6A) were incubated with immobilized glutathione S-transferase fused with the cytoplasmic tail of nephrin (GST–nephrinICD).

nephrin Binding (complex) of PAR3 in tail

5) Confidence 0.30 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2614475 Disease Relevance 0 Pain Relevance 0

This indicates that CT11 partly mediates the interaction between nephrin with PAR3, and is consistent with the sequence similarity of CT11 to the type II PDZ-binding motif [29], [30].

nephrin Binding (interaction) of PAR3

6) Confidence 0.30 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2614475 Disease Relevance 0 Pain Relevance 0

The aPKC–PAR3 complex associates with the nephrin–podocin complex in podocytes through direct interaction between PAR3 and nephrin, and the kinase activity of aPKC is required for the appropriate distribution of nephrin and podocin in podocytes.

nephrin Binding (associates) of PAR3 in podocytes

7) Confidence 0.30 Published 2009 Journal PLoS ONE Section Abstract Doc Link PMC2614475 Disease Relevance 0.34 Pain Relevance 0.04

Furthermore, nephrin coprecipitated with PAR3 from both fractions.

nephrin Binding (coprecipitated) of PAR3

8) Confidence 0.30 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2614475 Disease Relevance 0 Pain Relevance 0

Our data further suggest that the association of the aPKC–PAR3 complex with the nephrin–podocin complex regulates the state of equilibrium in which nephrin and podocin are appropriately distributed among raft and non-raft microdomains to avoid unnecessary aggregation of nephrin.

nephrin Binding (complex) of PAR3

9) Confidence 0.29 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2614475 Disease Relevance 0 Pain Relevance 0

We next addressed the possibility of direct interaction between PAR3 and nephrin in vitro.

nephrin Binding (interaction) of PAR3

10) Confidence 0.29 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2614475 Disease Relevance 0 Pain Relevance 0

T7-tagged PAR3 mutants overexpressed in 293T cells specifically interacted with GST–nephrinICD, except for the mutants lacking all PDZ domains or mutated in the third PDZ domain [27], [28], indicating the third PDZ domain is required for the formation of the complex with nephrin (Figure 6B).

nephrinICD Binding (interacted) of PAR3

11) Confidence 0.29 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2614475 Disease Relevance 0 Pain Relevance 0

Our data further suggest that the association of the aPKC–PAR3 complex with the nephrin–podocin complex regulates the state of equilibrium in which nephrin and podocin are appropriately distributed among raft and non-raft microdomains to avoid unnecessary aggregation of nephrin.

nephrin Binding (association) of PAR3

12) Confidence 0.29 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2614475 Disease Relevance 0 Pain Relevance 0

Endogenous aPKC in 293T cells also interacted with GST–nephrinICD in a PAR3-dependent manner, confirming the formation of a ternary complex of PAR3, aPKC, and nephrin.

nephrinICD Binding (interacted) of PAR3

13) Confidence 0.29 Published 2009 Journal PLoS ONE Section Body Doc Link PMC2614475 Disease Relevance 0 Pain Relevance 0

The aPKC–PAR3 complex associates with the nephrin–podocin complex in podocytes through direct interaction between PAR3 and nephrin, and the kinase activity of aPKC is required for the appropriate distribution of nephrin and podocin in podocytes.

nephrin Binding (interaction) of PAR3 in podocytes

14) Confidence 0.29 Published 2009 Journal PLoS ONE Section Abstract Doc Link PMC2614475 Disease Relevance 0.33 Pain Relevance 0.04

General Comments

This test has worked.