Limits...
Direct signaling by the BMP type II receptor via the cytoskeletal regulator LIMK1.

Foletta VC, Lim MA, Soosairajah J, Kelly AP, Stanley EG, Shannon M, He W, Das S, Massague J, Bernard O, Soosairaiah J - J. Cell Biol. (2003)

Bottom Line: Further analysis revealed that the interaction between LIMK1 and BMPR-II inhibited LIMK1's ability to phosphorylate cofilin, which could then be alleviated by addition of BMP4.A BMPR-II mutant containing the smallest COOH-terminal truncation described in PPH failed to bind or inhibit LIMK1.This study identifies the first function of the BMPR-II tail domain and suggests that the deregulation of actin dynamics may contribute to the etiology of PPH.

View Article: PubMed Central - PubMed

Affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade Parkville, Victoria 3050, Australia.

ABSTRACT
Bone morphogenetic proteins (BMPs) regulate multiple cellular processes, including cell differentiation and migration. Their signals are transduced by the kinase receptors BMPR-I and BMPR-II, leading to Smad transcription factor activation via BMPR-I. LIM kinase (LIMK) 1 is a key regulator of actin dynamics as it phosphorylates and inactivates cofilin, an actin depolymerizing factor. During a search for LIMK1-interacting proteins, we isolated clones encompassing the tail region of BMPR-II. Although the BMPR-II tail is not involved in BMP signaling via Smad proteins, mutations truncating this domain are present in patients with primary pulmonary hypertension (PPH). Further analysis revealed that the interaction between LIMK1 and BMPR-II inhibited LIMK1's ability to phosphorylate cofilin, which could then be alleviated by addition of BMP4. A BMPR-II mutant containing the smallest COOH-terminal truncation described in PPH failed to bind or inhibit LIMK1. This study identifies the first function of the BMPR-II tail domain and suggests that the deregulation of actin dynamics may contribute to the etiology of PPH.

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Schematic representation of two signaling outputs from the BMPR system. In the canonical Smad signaling process, BMP4 binds to and brings together BMPR-I (-IA or -IB, also known as ALK3 and ALK6, respectively) and BMPR-II. BMPR-II phosphorylates the regulatory region (green box) of BMPR-I, activating the kinase domain (blue box), which phosphorylates Smad1, leading to its nuclear translocation for regulation of target genes. The present results show that the COOH-terminal tail domain (yellow box) of BMPR-II in the basal state binds to the LIM domain region of LIMK1 and inhibits LIMK1. BMP4 binding relieves this inhibitory interaction, enabling LIMK1 to phosphorylate cofilin, thereby regulating the actin cytoskeleton.
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fig6: Schematic representation of two signaling outputs from the BMPR system. In the canonical Smad signaling process, BMP4 binds to and brings together BMPR-I (-IA or -IB, also known as ALK3 and ALK6, respectively) and BMPR-II. BMPR-II phosphorylates the regulatory region (green box) of BMPR-I, activating the kinase domain (blue box), which phosphorylates Smad1, leading to its nuclear translocation for regulation of target genes. The present results show that the COOH-terminal tail domain (yellow box) of BMPR-II in the basal state binds to the LIM domain region of LIMK1 and inhibits LIMK1. BMP4 binding relieves this inhibitory interaction, enabling LIMK1 to phosphorylate cofilin, thereby regulating the actin cytoskeleton.

Mentions: The primary function of LIMK1 identified so far is to regulate actin dynamics by phosphorylating cofilin (Arber et al., 1998; Yang et al., 1998). We have shown that BMPR-II associates with LIMK proteins and subsequently reduces LIMK1's ability to phosphorylate cofilin, suggesting that BMPR-II molecules negatively regulate the activity of LIMK1. How BMPR-II inhibits the activity of LIMK1 is not yet clear. It is possible that the binding of LIMK1 via its LIM domains to the tail of BMPR-II reduces its availability in the cytoplasm and limits its access to its activators PAK and ROCK, as we have demonstrated here for PAK4. Significantly, this inhibitory effect appears to be alleviated by BMP4 stimulation. It is possible that upon engagement of the BMP4 ligand by BMPR-II, followed by formation of BMP–BMPR-II–BMPR-IA complex, LIMK1 is dissociated from the BMPR-II tail, enabling it to more freely interact with other proteins, such as its activators, resulting in cofilin phosphorylation (Fig. 6).


Direct signaling by the BMP type II receptor via the cytoskeletal regulator LIMK1.

Foletta VC, Lim MA, Soosairajah J, Kelly AP, Stanley EG, Shannon M, He W, Das S, Massague J, Bernard O, Soosairaiah J - J. Cell Biol. (2003)

Schematic representation of two signaling outputs from the BMPR system. In the canonical Smad signaling process, BMP4 binds to and brings together BMPR-I (-IA or -IB, also known as ALK3 and ALK6, respectively) and BMPR-II. BMPR-II phosphorylates the regulatory region (green box) of BMPR-I, activating the kinase domain (blue box), which phosphorylates Smad1, leading to its nuclear translocation for regulation of target genes. The present results show that the COOH-terminal tail domain (yellow box) of BMPR-II in the basal state binds to the LIM domain region of LIMK1 and inhibits LIMK1. BMP4 binding relieves this inhibitory interaction, enabling LIMK1 to phosphorylate cofilin, thereby regulating the actin cytoskeleton.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172847&req=5

fig6: Schematic representation of two signaling outputs from the BMPR system. In the canonical Smad signaling process, BMP4 binds to and brings together BMPR-I (-IA or -IB, also known as ALK3 and ALK6, respectively) and BMPR-II. BMPR-II phosphorylates the regulatory region (green box) of BMPR-I, activating the kinase domain (blue box), which phosphorylates Smad1, leading to its nuclear translocation for regulation of target genes. The present results show that the COOH-terminal tail domain (yellow box) of BMPR-II in the basal state binds to the LIM domain region of LIMK1 and inhibits LIMK1. BMP4 binding relieves this inhibitory interaction, enabling LIMK1 to phosphorylate cofilin, thereby regulating the actin cytoskeleton.
Mentions: The primary function of LIMK1 identified so far is to regulate actin dynamics by phosphorylating cofilin (Arber et al., 1998; Yang et al., 1998). We have shown that BMPR-II associates with LIMK proteins and subsequently reduces LIMK1's ability to phosphorylate cofilin, suggesting that BMPR-II molecules negatively regulate the activity of LIMK1. How BMPR-II inhibits the activity of LIMK1 is not yet clear. It is possible that the binding of LIMK1 via its LIM domains to the tail of BMPR-II reduces its availability in the cytoplasm and limits its access to its activators PAK and ROCK, as we have demonstrated here for PAK4. Significantly, this inhibitory effect appears to be alleviated by BMP4 stimulation. It is possible that upon engagement of the BMP4 ligand by BMPR-II, followed by formation of BMP–BMPR-II–BMPR-IA complex, LIMK1 is dissociated from the BMPR-II tail, enabling it to more freely interact with other proteins, such as its activators, resulting in cofilin phosphorylation (Fig. 6).

Bottom Line: Further analysis revealed that the interaction between LIMK1 and BMPR-II inhibited LIMK1's ability to phosphorylate cofilin, which could then be alleviated by addition of BMP4.A BMPR-II mutant containing the smallest COOH-terminal truncation described in PPH failed to bind or inhibit LIMK1.This study identifies the first function of the BMPR-II tail domain and suggests that the deregulation of actin dynamics may contribute to the etiology of PPH.

View Article: PubMed Central - PubMed

Affiliation: The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade Parkville, Victoria 3050, Australia.

ABSTRACT
Bone morphogenetic proteins (BMPs) regulate multiple cellular processes, including cell differentiation and migration. Their signals are transduced by the kinase receptors BMPR-I and BMPR-II, leading to Smad transcription factor activation via BMPR-I. LIM kinase (LIMK) 1 is a key regulator of actin dynamics as it phosphorylates and inactivates cofilin, an actin depolymerizing factor. During a search for LIMK1-interacting proteins, we isolated clones encompassing the tail region of BMPR-II. Although the BMPR-II tail is not involved in BMP signaling via Smad proteins, mutations truncating this domain are present in patients with primary pulmonary hypertension (PPH). Further analysis revealed that the interaction between LIMK1 and BMPR-II inhibited LIMK1's ability to phosphorylate cofilin, which could then be alleviated by addition of BMP4. A BMPR-II mutant containing the smallest COOH-terminal truncation described in PPH failed to bind or inhibit LIMK1. This study identifies the first function of the BMPR-II tail domain and suggests that the deregulation of actin dynamics may contribute to the etiology of PPH.

Show MeSH
Related in: MedlinePlus