Noncanonical Myo9b-RhoGAP Accelerates RhoA GTP Hydrolysis by a Dual-Arginine-Finger Mechanism

Yi, Facheng; Kong, Ruirui; Ren, Jinqi; Zhu, Li; Lou, Jizhong; Wu, Jane Y.; Feng, Wei

doi:10.1016/j.jmb.2016.06.014

Cited by 17 publications

(11 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Myo9A, actin and calmodulin. These findings support the interpretation that Myo9A haploinsufficiency is the basis for the reduced Myo9A-actin-calmodulin interaction observed in 9,53 RhoGAP loss of function increases Rho-GTPase activity and leads to podocyte injury, proteinuria and FSGS. 3,18,20 Thus, the abnormal behavior of Myo9A R701X/+ mutant podocytes may contribute to the development of foot process effacement and FSGS over time in Myo9A R701X/+ mice.…”

Section: J O U R N a L P R E -P R O O Fsupporting

confidence: 85%

Rho-GTPase Activating Protein myosin MYO9A identified as a novel candidate gene for monogenic focal segmental glomerulosclerosis

Gulati

Lemaire

et al. 2021

Kidney International

View full text Add to dashboard Cite

Section: J O U R N a L P R E -P R O O Fsupporting

confidence: 85%

Rho-GTPase Activating Protein myosin MYO9A identified as a novel candidate gene for monogenic focal segmental glomerulosclerosis

Gulati

Lemaire

et al. 2021

Kidney International

View full text Add to dashboard Cite

“…The RhoGAP myosin IXb (Myo9b) accumulates in protrusive cellular structures containing dynamic actin filaments owing to its actin-based motor activity ( 15 ). Deletion of Myo9b causes impaired cell migration both in vitro and in vivo ( 16 , 17 , 18 , 19 , 20 ). We hypothesized that Myo9b is recruited to extending lamellipodia through Rac-induced actin polymerization to locally inhibit RhoA activity at the leading edge.…”

mentioning

confidence: 99%

Local Myo9b RhoGAP activity regulates cell motility

Hemkemeyer¹,

Vollmer²,

Schwarz³

et al. 2021

Journal of Biological Chemistry

View full text Add to dashboard Cite

To migrate, cells assume a polarized morphology, extending forward with a leading edge with their trailing edge retracting back toward the cell body. Both cell extension and retraction critically depend on the organization and dynamics of the actin cytoskeleton, and the small, monomeric GTPases Rac and Rho are important regulators of actin. Activation of Rac induces actin polymerization and cell extension whereas activation of Rho enhances acto-myosin II contractility and cell retraction. To coordinate migration, these processes must be carefully regulated. The myosin Myo9b, a Rho GTPase activating protein (GAP), negatively regulates Rho activity and deletion of Myo9b in leukocytes impairs cell migration through increased Rho activity. However, it is not known whether cell motility is regulated by global or local inhibition of Rho activity by Myo9b. Here, we addressed this question by using Myo9b-deficient macrophage-like cells that expressed different recombinant Myo9b constructs. We found that Myo9b accumulates in lamellipodial extensions generated by Rac-induced actin polymerization as a function of its motor activity. Deletion of Myo9b in HL-60 derived macrophages altered cell morphology and impaired cell migration. Reintroduction of Myo9b or Myo9b motor and GAP mutants revealed that local GAP activity rescues cell morphology and migration. In summary, Rac activation leads to actin polymerization and recruitment of Myo9b, which locally inhibits Rho activity to enhance directional cell migration. In summary, Rac activation leads to actin polymerization and recruitment of Myo9b, which locally inhibits Rho activity to enhance directional cell migration.

show abstract

“…An important finding of this work is that SNO-RhoA occurs in normal podocytes and inversely relates with RhoA activity. Myo9A interacts directly with RhoA through its tail RhoGAP domain ( 14 , 28 ). Upon binding, Myo9A dephosphorylates RhoA GTPase rendering it inactive ( 14 ).…”

Section: Discussionmentioning

confidence: 99%

“…Since Myo9A directly interacts with both actin and RhoA ( 27 , 28 ), we hypothesized that Myo9A might undergo S-nitrosylation and thereby participate in a transnitrosylation cascade to serve NO signaling. The goals of this study were to determine whether Myo9A dysregulation is involved in the severity of DKD and to assess whether the molecular mechanism involves Myo9A S-nitrosylation.…”

Section: Introductionmentioning

confidence: 99%

S-Nitrosylation of RhoGAP Myosin9A Is Altered in Advanced Diabetic Kidney Disease

Li¹,

Verón²,

Tufró

2021

Front. Med.

View full text Add to dashboard Cite

The molecular pathogenesis of diabetic kidney disease progression is complex and remains unresolved. Rho-GAP MYO9A was recently identified as a novel podocyte protein and a candidate gene for monogenic FSGS. Myo9A involvement in diabetic kidney disease has been suggested. Here, we examined the effect of diabetic milieu on Myo9A expression in vivo and in vitro. We determined that Myo9A undergoes S-nitrosylation, a post-translational modification dependent on nitric oxide (NO) availability. Diabetic mice with nodular glomerulosclerosis and severe proteinuria associated with doxycycline-induced, podocyte-specific VEGF164 gain-of-function showed markedly decreased glomerular Myo9A expression and S-nitrosylation, as compared to uninduced diabetic mice. Immortalized mouse podocytes exposed to high glucose revealed decreased Myo9A expression, assessed by qPCR, immunoblot and immunocytochemistry, and reduced Myo9A S-nitrosylation (SNO-Myo9A), assessed by proximity link assay and biotin switch test, functionally resulting in abnormal podocyte migration. These defects were abrogated by exposure to a NO donor and were not due to hyperosmolarity. Our data demonstrate that high-glucose induced decrease of both Myo9A expression and SNO-Myo9A is regulated by NO availability. We detected S-nitrosylation of Myo9A interacting proteins RhoA and actin, which was also altered by high glucose and NO dependent. RhoA activity inversely related to SNO-RhoA. Collectively, data suggest that dysregulation of SNO-Myo9A, SNO-RhoA and SNO-actin may contribute to the pathogenesis of advanced diabetic kidney disease and may be amenable to therapeutic targeting.

show abstract

Noncanonical Myo9b-RhoGAP Accelerates RhoA GTP Hydrolysis by a Dual-Arginine-Finger Mechanism

Cited by 17 publications

References 42 publications

Rho-GTPase Activating Protein myosin MYO9A identified as a novel candidate gene for monogenic focal segmental glomerulosclerosis

Rho-GTPase Activating Protein myosin MYO9A identified as a novel candidate gene for monogenic focal segmental glomerulosclerosis

Local Myo9b RhoGAP activity regulates cell motility

S-Nitrosylation of RhoGAP Myosin9A Is Altered in Advanced Diabetic Kidney Disease

Contact Info

Product

Resources

About