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Pathophysiological Functions of Rnd3/RhoE

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ABSTRACT

Rnd3, also known as RhoE, belongs to the Rnd subclass of the Rho family of small guanosine triphosphate (GTP)‐binding proteins. Rnd proteins are unique due to their inability to switch from a GTP‐bound to GDP‐bound conformation. Even though studies of the biological function of Rnd3 are far from being concluded, information is available regarding its expression pattern, cellular localization, and its activity, which can be altered depending on the conditions. The compiled data from these studies implies that Rnd3 may not be a traditional small GTPase. The basic role of Rnd3 is to report as an endogenous antagonist of RhoA signaling‐mediated actin cytoskeleton dynamics, which specifically contributes to cell migration and neuron polarity. In addition, Rnd3 also plays a critical role in arresting cell cycle distribution, inhibiting cell growth, and inducing apoptosis and differentiation. Increasing data have shown that aberrant Rnd3 expression may be the leading cause of some systemic diseases; particularly highlighted in apoptotic cardiomyopathy, developmental arrhythmogenesis and heart failure, hydrocephalus, as well as tumor metastasis and chemotherapy resistance. Therefore, a better understanding of the function of Rnd3 under different physiological and pathological conditions, through the use of suitable models, would provide a novel insight into the origin and treatment of multiple human diseases. © 2016 American Physiological Society. Compr Physiol 6:169‐186, 2016.

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Figure 1. Figure 1. Rnd3 mediates actin cytoskeletal dynamics. The switching of the GDP‐bound to the GTP‐bound RhoA form is a basic mechanism that mediates RhoA/ROCK1 signaling. Rnd3 promotes p190RhoGAP to hydrolyze the active GTP‐bound form into the resting GDP‐bound RhoA. Additionally, Rnd3 directly binds with ROCK1 and suppresses RhoA/ROCK1 signaling. MLC: myosin light chain; Dia: diaphanous; PLD: phospholipase D; PA: phosphatidic acid.
Figure 2. Figure 2. Rnd3 mediates neuron polarization. (A) In Rnd3 WT neurons, intracellular stimuli induced dendrite and axon outgrowth with actin rearrangement (126). (B) In Rnd3‐null neurons, the intracellular stimuli induced cell polarization but was delayed. This was evidenced by a reduction in the number of dendrites and shortened lengths of the axons. Figure 2A was adapted, with permission, from Ref. (140140).
Figure 3. Figure 3. Rnd3 mediates apoptosis. (A) Rnd3 is involved in apoptosis through ROCK1‐dependent and ‐independent manners. (B) The ROCK1‐dependent mechanism refers to attenuation of apoptosis through direct inhibition of ROCK1 activation by Rnd3. (C) The ROCK1‐independent mechanism means that Rnd3 is involved in apoptosis through mediation of caspase3, BAX, Rb, plaloglobin, and BCL‐2.
Figure 4. Figure 4. Rnd3 mediates the cell cycle. (A) The cell cycle includes the transition from the G1 to S phase followed by the G2 to M phase transition. Upon stimulation, the cell enters the cell cycle going from the G0 to G1 stage. The appropriate stimuli lead to cell cycle completion; resulting in the production of two daughter cells. In each stage, special cyclins bind with cyclin kinase (CDK) to drive the progression of the cell cycle. This progression is inhibited by cyclin kinase inhibitor (CDI). M stage refers to mitosis in which two daughter cells are produced, the preceding stages can be referred to as interphase. (B) Rnd3 arrests the cell cycle at the G1 stage. Upon receiving a promitotic extracellular signal, cyclin D binds with CDK4 and CDK6. As a result, low levels of phosphorylated pRb protein are phosphorylated into a hyperphosphorylated condition. Next, the hyperphosphorylated pRb release the nuclear transcription factor E2F from the E2F/DP1/Rb complex. The free E2F drives downstream gene expression including cyclin E, cyclin A, DNA polymerase, thymidine kinase, etc. The increasing cyclin E binds with CDK2 to further phosphorylate pRb and push the cell cycle from the G1 to S phase. In this stage, Rnd3 attenuates cyclin D and p21 expression and arrests the cell cycle at the G1 stage. (C) In the G2/M stage, Rnd3 attenuates CDK1 and cyclin B expression and therefore arrests the cell cycle at the G2/M stage. CHK1: checkpoint kinase 1; WEE1: a kind of mitosis inhibitor kinase; CDC25: cell division cycle 25, a dual‐specificity phosphatase.
Figure 5. Figure 5. E10.5 embryos with H&E staining show no obvious morphological defects in the Rnd3‐null heart. Rnd3 WT E10.5 mouse heart coronal (A) and sagittal (C) sections, Rnd3−/− E10.5 mouse heart coronal (B) and sagittal (D) sections. EC: endocardial cushion; RV: right ventricle; LV: left ventricle; OFT: outflow tract; IVS: interventricular septum; VT: ventricular; AT: atrium; AVC: AV canal. Objective lens: 10X. This figure was published as Figure S1 in Ref. (145) and republished with press authorization.
Figure 6. Figure 6. Rnd3 involvement in overpressure‐induced cardiomyocyte apoptosis and heart failure. After TAC surgery, full length 160 kDa ROCK1 was cleaved into 130 kDa pieces. This cleaved ROCK1 promotes cardiomyocyte apoptosis and therefore leads to heart failure. Fasudil, a chemical inhibitor of ROCK1, attenuates TAC‐promoted apoptosis and heart failure. Rnd3, the endogenous ROCK1 inhibitor, may directly attenuate ROCK1‐induced apoptosis and may also inhibit apoptosis through a ROCK1‐indendent manner, however, it remains unknown. For more details, please refer to our published articles; Ref. (20) and (147).
Figure 7. Figure 7. Proposed model outlining the molecular mechanism of the Rnd3 deficiency‐mediated calcium dysregulation. Downregulation of Rnd3 attenuated β2‐adrenergic receptor (β2AR) lysosomal targeting and ubiquitination, which in turn resulted in elevated β2AR protein levels and led to hyperactivation of protein kinase A (PKA) signaling. The PKA activation destabilized ryanodine receptor type 2 (RyR2) Ca2+ release channels, contributing to calcium leakage. This figure was published in ref. (145) and republished with press authorization.
Figure 8. Figure 8. A proposed model outlining the molecular mechanism of Rnd3 deficiency‐mediated hydrocephalus development. (A) Upon activation, Notch receptors on ependymal cell membranes are cleaved into NICD, an intracellular isoform, which is translocated into the nucleus. In the nucleus, Rnd3 controls NICD protein accessibility to MAML and CSL through physical interaction with NICD. In the absence of Rnd3, Notch signaling is significantly enhanced due to the extra amount of NICD available for MAML and CSL to form transcriptomes; which facilitates ependymal cell proliferation resulting in aqueductal stenosis and hydrocephalus. (B) Illustrations of aqueductal stenosis formation. Depletion of Rnd3 promotes ependymal cell proliferation through an enhanced Notch signaling mechanism. The overgrowth of ependymal cells leads to the formation of multiple ependymal cell layers, inward cellular folding, and eventually luminal stenosis or closure. This figure was published as Figure 7 in Ref. (78) and republished with press authorization.
Figure 9. Figure 9. Rnd3 antagonizes RhoA/MOCK1 signaling during various stages of pregnancy. (A) In the nonpregnant rabbit uterus, constitutively expressed Rnd3 antagonizes RhoA/MOCK1 signaling which maintains the smooth muscle cells of the uterus in the quiescent state. (B) During the mid‐pregnancy stage (15 days) in the rabbit uterus, upregulated Rnd3 antagonizes enhanced RhoA/MOCK1 signaling and maintains the calcium‐dependent increase in Ca2+ MLCK and tension at a higher level (Ca2+ sensitization). This effect can be recovered by treatment of muscle strips from mid‐pregnancy myometrium with farnesyl‐transferase inhibitor, Manumycin A. (C) During late pregnancy (31 days), upregulation of RhoA and Rho kinase expression is associated with an increase in Ca2+ sensitivity of contractile proteins that is inhibited by the Rho kinase inhibitor, Y‐27632. MLC: myosin light chain; Ca2+‐MLCK: Ca2+‐calmodulin‐activated myosin light chain kinase; MCLP: myosin light chain phosphatase.
Figure 10. Figure 10. Rnd3 phosphorylation and degradation. Unphosphorylated Rnd3 binds to the cell membrane and is degraded through the ubiquitin/proteasome system. PMA‐activated PKCα and LPA‐activated ROCK1 promote the phosphorylation of Rnd3. The phosphorylation of Rnd3 enhances its stability and causes its translocation into the cytoplasm where it is resistant to ubiquitination/proteasome system degradation. The phosphorylated Rnd3 also binds with ROCK1 and therefore attenuates ROCK1 functions. PMA: phorbol 12‐myristate‐13‐acetate; PDGF: platelet‐derived growth factor; LPA: lysophosphatidic acid (117).
Figure 11. Figure 11. PlexinB2 and Rnd3 competitively bind to p190RhoGAP. Rnd3 promotes p190RhoGAP activity and therefore promotes hydrolyzation of GTP to GDP, which in turn attenuates RhoA/ROCK1 signaling. As a receptor of semaphoring, PlexinB2 competitively binds to p190RhoGAP and inhibits p190RhoGAP activity; subsequently driving neuron migration and axonal outgrowth.


Figure 1. Rnd3 mediates actin cytoskeletal dynamics. The switching of the GDP‐bound to the GTP‐bound RhoA form is a basic mechanism that mediates RhoA/ROCK1 signaling. Rnd3 promotes p190RhoGAP to hydrolyze the active GTP‐bound form into the resting GDP‐bound RhoA. Additionally, Rnd3 directly binds with ROCK1 and suppresses RhoA/ROCK1 signaling. MLC: myosin light chain; Dia: diaphanous; PLD: phospholipase D; PA: phosphatidic acid.


Figure 2. Rnd3 mediates neuron polarization. (A) In Rnd3 WT neurons, intracellular stimuli induced dendrite and axon outgrowth with actin rearrangement (126). (B) In Rnd3‐null neurons, the intracellular stimuli induced cell polarization but was delayed. This was evidenced by a reduction in the number of dendrites and shortened lengths of the axons. Figure 2A was adapted, with permission, from Ref. (140140).


Figure 3. Rnd3 mediates apoptosis. (A) Rnd3 is involved in apoptosis through ROCK1‐dependent and ‐independent manners. (B) The ROCK1‐dependent mechanism refers to attenuation of apoptosis through direct inhibition of ROCK1 activation by Rnd3. (C) The ROCK1‐independent mechanism means that Rnd3 is involved in apoptosis through mediation of caspase3, BAX, Rb, plaloglobin, and BCL‐2.


Figure 4. Rnd3 mediates the cell cycle. (A) The cell cycle includes the transition from the G1 to S phase followed by the G2 to M phase transition. Upon stimulation, the cell enters the cell cycle going from the G0 to G1 stage. The appropriate stimuli lead to cell cycle completion; resulting in the production of two daughter cells. In each stage, special cyclins bind with cyclin kinase (CDK) to drive the progression of the cell cycle. This progression is inhibited by cyclin kinase inhibitor (CDI). M stage refers to mitosis in which two daughter cells are produced, the preceding stages can be referred to as interphase. (B) Rnd3 arrests the cell cycle at the G1 stage. Upon receiving a promitotic extracellular signal, cyclin D binds with CDK4 and CDK6. As a result, low levels of phosphorylated pRb protein are phosphorylated into a hyperphosphorylated condition. Next, the hyperphosphorylated pRb release the nuclear transcription factor E2F from the E2F/DP1/Rb complex. The free E2F drives downstream gene expression including cyclin E, cyclin A, DNA polymerase, thymidine kinase, etc. The increasing cyclin E binds with CDK2 to further phosphorylate pRb and push the cell cycle from the G1 to S phase. In this stage, Rnd3 attenuates cyclin D and p21 expression and arrests the cell cycle at the G1 stage. (C) In the G2/M stage, Rnd3 attenuates CDK1 and cyclin B expression and therefore arrests the cell cycle at the G2/M stage. CHK1: checkpoint kinase 1; WEE1: a kind of mitosis inhibitor kinase; CDC25: cell division cycle 25, a dual‐specificity phosphatase.


Figure 5. E10.5 embryos with H&E staining show no obvious morphological defects in the Rnd3‐null heart. Rnd3 WT E10.5 mouse heart coronal (A) and sagittal (C) sections, Rnd3−/− E10.5 mouse heart coronal (B) and sagittal (D) sections. EC: endocardial cushion; RV: right ventricle; LV: left ventricle; OFT: outflow tract; IVS: interventricular septum; VT: ventricular; AT: atrium; AVC: AV canal. Objective lens: 10X. This figure was published as Figure S1 in Ref. (145) and republished with press authorization.


Figure 6. Rnd3 involvement in overpressure‐induced cardiomyocyte apoptosis and heart failure. After TAC surgery, full length 160 kDa ROCK1 was cleaved into 130 kDa pieces. This cleaved ROCK1 promotes cardiomyocyte apoptosis and therefore leads to heart failure. Fasudil, a chemical inhibitor of ROCK1, attenuates TAC‐promoted apoptosis and heart failure. Rnd3, the endogenous ROCK1 inhibitor, may directly attenuate ROCK1‐induced apoptosis and may also inhibit apoptosis through a ROCK1‐indendent manner, however, it remains unknown. For more details, please refer to our published articles; Ref. (20) and (147).


Figure 7. Proposed model outlining the molecular mechanism of the Rnd3 deficiency‐mediated calcium dysregulation. Downregulation of Rnd3 attenuated β2‐adrenergic receptor (β2AR) lysosomal targeting and ubiquitination, which in turn resulted in elevated β2AR protein levels and led to hyperactivation of protein kinase A (PKA) signaling. The PKA activation destabilized ryanodine receptor type 2 (RyR2) Ca2+ release channels, contributing to calcium leakage. This figure was published in ref. (145) and republished with press authorization.


Figure 8. A proposed model outlining the molecular mechanism of Rnd3 deficiency‐mediated hydrocephalus development. (A) Upon activation, Notch receptors on ependymal cell membranes are cleaved into NICD, an intracellular isoform, which is translocated into the nucleus. In the nucleus, Rnd3 controls NICD protein accessibility to MAML and CSL through physical interaction with NICD. In the absence of Rnd3, Notch signaling is significantly enhanced due to the extra amount of NICD available for MAML and CSL to form transcriptomes; which facilitates ependymal cell proliferation resulting in aqueductal stenosis and hydrocephalus. (B) Illustrations of aqueductal stenosis formation. Depletion of Rnd3 promotes ependymal cell proliferation through an enhanced Notch signaling mechanism. The overgrowth of ependymal cells leads to the formation of multiple ependymal cell layers, inward cellular folding, and eventually luminal stenosis or closure. This figure was published as Figure 7 in Ref. (78) and republished with press authorization.


Figure 9. Rnd3 antagonizes RhoA/MOCK1 signaling during various stages of pregnancy. (A) In the nonpregnant rabbit uterus, constitutively expressed Rnd3 antagonizes RhoA/MOCK1 signaling which maintains the smooth muscle cells of the uterus in the quiescent state. (B) During the mid‐pregnancy stage (15 days) in the rabbit uterus, upregulated Rnd3 antagonizes enhanced RhoA/MOCK1 signaling and maintains the calcium‐dependent increase in Ca2+ MLCK and tension at a higher level (Ca2+ sensitization). This effect can be recovered by treatment of muscle strips from mid‐pregnancy myometrium with farnesyl‐transferase inhibitor, Manumycin A. (C) During late pregnancy (31 days), upregulation of RhoA and Rho kinase expression is associated with an increase in Ca2+ sensitivity of contractile proteins that is inhibited by the Rho kinase inhibitor, Y‐27632. MLC: myosin light chain; Ca2+‐MLCK: Ca2+‐calmodulin‐activated myosin light chain kinase; MCLP: myosin light chain phosphatase.


Figure 10. Rnd3 phosphorylation and degradation. Unphosphorylated Rnd3 binds to the cell membrane and is degraded through the ubiquitin/proteasome system. PMA‐activated PKCα and LPA‐activated ROCK1 promote the phosphorylation of Rnd3. The phosphorylation of Rnd3 enhances its stability and causes its translocation into the cytoplasm where it is resistant to ubiquitination/proteasome system degradation. The phosphorylated Rnd3 also binds with ROCK1 and therefore attenuates ROCK1 functions. PMA: phorbol 12‐myristate‐13‐acetate; PDGF: platelet‐derived growth factor; LPA: lysophosphatidic acid (117).


Figure 11. PlexinB2 and Rnd3 competitively bind to p190RhoGAP. Rnd3 promotes p190RhoGAP activity and therefore promotes hydrolyzation of GTP to GDP, which in turn attenuates RhoA/ROCK1 signaling. As a receptor of semaphoring, PlexinB2 competitively binds to p190RhoGAP and inhibits p190RhoGAP activity; subsequently driving neuron migration and axonal outgrowth.
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Wei Jie, Kelsey C. Andrade, Xi Lin, Xiangsheng Yang, Xiaojing Yue, Jiang Chang. Pathophysiological Functions of Rnd3/RhoE. Compr Physiol 2015, 6: 169-186. doi: 10.1002/cphy.c150018