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American Journal of Respiratory Cell and Molecular Biology. Vol. 28, pp. 546-550, 2003
© 2003 American Thoracic Society
DOI: 10.1165/rcmb.F267

Perspective

Lymphangioleiomyomatosis

A Complex Tale of Serum Response Factor–Mediated Tissue Inhibitor of Metalloproteinase-3 Regulation

Vera P. Krymskaya and J. Michael Shipley*

Pulmonary, Allergy, and Critical Care Division, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; and Pulmonary and Critical Care Division, Departments of Medicine, Cell Biology, and Physiology, Washington University School of Medicine, St. Louis, Missouri

Address correspondence to: Vera P. Krymskaya, Pulmonary, Allergy and Critical Care Division, Department of Medicine, University of Pennsylvania, 421 Curie Boulevard, 847 BRB II/III, Philadelphia, PA 19104-6160. E-mail: krymskay{at}mail.med.upenn.edu

Abbreviations: 4E-binding protein 1, 4E-BP1 • chronic obstructive pulmonary disease, COPD • GTPase-activating protein, GAP • lymphangioleiomyomatosis, LAM • matrix metalloproteinase, MMP • mammalian target of rapamycin, mTOR • S6 kinase, S6K1 • smooth muscle cell, SMC • serum response factor, SRF • tissue inhibitor of metalloproteinase, TIMP • tuberous sclerosis, TS


   Introduction
Top
 Introduction
Tuberin-A Multifunctional...
 Relevance of MMPs and...
 A Putative Link Between...
 References
 
In the last few years substantial progress has been made in understanding the pathobiology of lymphangioleiomyomatosis (LAM), from identifying the gene associated with the disease, to linking its cellular function to regulating cell proliferation. LAM is a rare lung disease affecting primarily women of childbearing age. It is characterized by the abnormal proliferation of smooth muscle–like cells, which leads to the cystic destruction of the lungs and loss of pulmonary function (1, 2). LAM can be sporadic or manifested in association with tuberous sclerosis (TS), an autosomal dominant inherited disorder affecting 1 in 6,000 individuals, who develop hamartomas and benign tumors in the brain, heart, and kidney, and it may also be manifested by cognitive defects, epilepsy, and autism (3, 4, 5). LAM was considered an "orphan" life-threatening disease of unknown etiology, with uncertain clinical prognosis and no proven treatment. The key advance came with the discovery that somatic mutation of the tumor suppressor gene TSC2 (tuberous sclerosis complex 2, tuberin) was associated with abnormal proliferation, differentiation, and migration of smooth muscle–like cells in the lungs of patients with LAM (6). This study established the genetic link between LAM and TS, and identified the critical role of the TSC2 gene in the etiology of LAM. In a paper by Zhe and coworkers in the April issue of the AJRCMB, additional pieces were added to this puzzle (7). They describe that serum response factor (SRF), which is normally expressed in immature smooth muscle cells (SMC), is abnormally induced in the SMC-like LAM cells. It appears that SRF potentially controls expression of a number of relevant genes in LAM cells, including the matrix metalloproteinases (MMPs)-2 and -14, as well as tissue inhibitor of metalloproteinase (TIMP)-3, an in vivo inhibitor of MMP activity. This study begins to forge a connection between tuberin, the tumor suppressor dysregulated in LAM, and effector molecules that are likely relevant to the cystic airspace enlargement that is a hallmark of LAM.


   Tuberin-A Multifunctional Regulator of Cell Proliferation
Top
 Introduction
 Tuberin-A Multifunctional...
Relevance of MMPs and...
 A Putative Link Between...
 References
 
Mutations of the TSC2 gene, which has a complex genomic structure comprising 41 exons and small-sized introns (8), are associated with tumor development in patients with LAM and in patients with TS. The mutations are found throughout the gene, without predominant localization to a specific region (3). The genetic evidence suggested that tuberin, a protein encoded by the TSC2 gene, is critically important for regulating cell proliferation, and that the loss or mutation of tuberin is associated with the abnormal cell proliferation seen in LAM and TS. Tuberin, a 198-kD, ubiquitously expressed, evolutionarily conserved protein, has identifiable structure-functional domains that might be important for its function as a tumor suppressor. One such domain has a small region of similarity with the GTPase-activating protein (GAP) Rap1 GAP or Rab5 (9–11). Tuberin also has two transcription-activating domains (12), a calmodulin-binding domain (13), and a hamartin-binding domain (14, 15) (reviewed in Ref. 16). The identification of GAP activity of tuberin, and the notion that loss or mutation of tuberin GAP activity may result in the constitutive activation of Rap1A or Rab5, gave rise to the speculation that tuberin may act as a tumor suppressor similar to the tumor suppressor NF-1, which has GAP activity for the proto-oncogene Ras (17). Although it is an attractive hypothesis, it remains to be demonstrated whether Rab5 or Rap1A is constitutively active due to tuberin mutations in LAM and TS lesions.

Recently, it has become increasingly clearer how tuberin affects the proliferation state of SMC-like cells in LAM, when it was demonstrated that tuberin is the master inhibitor of the S6 kinase (S6K1) signaling pathway (18). This conclusion is based on the observations that S6K1 is constitutively active in LAM cells with somatic mutations of TSC2, and that overexpression of tuberin in these cells inhibits activation of S6K1 (18). Growth factor–induced activation of S6K1 and its subsequent phosphorylation of ribosomal protein S6 are required for the biosynthesis of the cellular translational apparatus, specifically for ribosomes, critical components of cell growth and proliferation (19–21). For example, conditional deletion of the S6 gene in the liver of adult mice abrogates cell proliferation and cyclin E expression (22). The central role of S6K1 and ribosomal protein S6 in cellular proliferation has been further demonstrated by the use of rapamycin, a macrolide which specifically and directly inhibits the mammalian target of rapamycin (mTOR), an obligated upstream activator of S6K1 (20).

Tuberin controls cell growth and proliferation by negatively regulating the activity of S6K1 and the phosphorylation of the eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), potentially through their upstream modulator mTOR (Figure 1) (reviewed in Refs. 16, 23). Growth factors and insulin promote Akt/PKB-dependent phosphorylation of tuberin, which, in turn, releases S6K1 and 4E-BP1 from negative regulation by tuberin and results in the activation of S6K1 and the phosphorylation of 4E-BP1. Phosphorylated tuberin binds 14-3-3 proteins (24–26), and downregulates the level of p27KIP1, an inhibitor of cyclin-dependent kinases (27). Further downstream, tuberin modulates the transcriptional activity of AP-1 and the steroid hormone receptor family (12, 13).



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  		Figure 1. A model illustrating a role of tuberin in regulating cell proliferation. In the cellular cytosol, tuberin exists in the form of a heteromer with the tumor suppressor hamartin. Upon growth factor or insulin stimulation, phosphatidylinositol 3-kinase (PI3K) activates phosphoinositide-dependent kinase-1 (PDK-1), which in turn activates the serine-threonine kinase Akt. This results in the phosphorylation of tuberin and release of S6K1 inhibition, leading to increased protein synthesis and cell proliferation.

 
Although loss or mutation of tuberin affects diverse organ systems, neoplastic cell growth predominantly localizes within target organs. Malignant tumors are rare and occur primarily in the kidney. The ostensibly metastatic nature of LAM disease has been suggested by recent clinical and genetic evidence. Identical mutations of the TSC2 gene were found in the tumor cells from the lungs and kidney of a patient with sporadic LAM, suggesting that both cells were derived from the same source, most likely from the angiomyolipoma by metastatic (invasive) spread from kidney into the lungs (28). Additionally, LAM recurrence was reported after single-lung transplantation in patients without renal angiomyolipoma, suggesting that LAM cells can metastasize from LAM lung into the transplanted lung (29).


   Relevance of MMPs and TIMPs to LAM and Cystic Lung Disease
Top
 Introduction
 Tuberin-A Multifunctional...
 Relevance of MMPs and...
A Putative Link Between...
 References
 
In addition to abnormal smooth muscle–like proliferation, LAM is also characterized by cystic airspace enlargement similar to that seen in advanced chronic obstructive pulmonary disease (COPD). As is thought to be the case in COPD, it is likely that these pathologic changes in LAM are mediated by an imbalance between matrix-degrading proteases and their endogenous inhibitors. MMPs are but one class of proteases capable of degrading extracellular matrix of the lung parenchyma, but they are likely relevant. Little is known about the spectrum of MMPs and their inhibitors elaborated in the LAM lung. Elastic fibers in LAM have been shown to be scant, and those that remain are often disrupted (30). MMP-2 is prominently expressed in LAM lung, whereas increases in MMP-1 and -9 have also been demonstrated (31). MMP-2 and -9 are known to have the ability to degrade elastin (32). MMP-14, a known activator of MMP-2, is also expressed in LAM (33). Expression profiling studies have been done by Smolarek and Geraci in which LAM lung was compared to normal lung (http://lam.uc.edu/html/SciNews.html). In these experiments, it is clear that a number of MMPs are induced in LAM, including MMP-1 (collagenase), MMP-9 (gelatinase B), MMP-2 (gelatinase A), MMP-11 (stromelysin-3), and MMP-19. In addition, two related proteases from the ADAMs family, ADAM-10 and ADAM-17 (tumor necrosis factor-{alpha}–converting enzyme), both contain a metalloprotease catalytic domain and are induced in LAM. In addition to an increase in protease expression, a number of extracellular matrix genes appear to be downregulated in LAM including laminins {alpha}3 and {gamma}2, the {alpha}2 chain of type IV collagen, and heparan sulfate proteoglycans.

In analogy to COPD, it would seem plausible that MMPs and their endogenous inhibitors, the TIMPs, are involved in matrix destruction that leads to airspace enlargement in LAM. Numerous studies have documented that MMPs-1, -2, -9, and -12, which collectively are capable of degrading fibrillar collagen and elastin, are overexpressed in macrophages in smokers with COPD, compared with nonsmokers or healthy smokers (reviewed in Ref. 34). In addition, smokers with COPD elaborate MMP-1 from type II pneumocytes as well (35). Recently, a number of linkage studies have begun to correlate MMP-related mutations with COPD. These studies have shown an association of MMP-1 and -12 (36), MMP-9 (37), and TIMP-2 (38) polymorphisms with COPD.

A number of studies using mouse models have shed light on the role of MMPs in emphysematous airspace enlargement. Mice lacking expression of MMP-12 (macrophage metalloelastase) do not develop emphysema when exposed to chronic cigarette smoke, in contrast to normal mice (39). Overexpression of collagenase (MMP-1) in the lungs of transgenic mice leads to progressive airspace enlargement (40). Inducible expression of either interferon-{gamma} (41) or interleukin-13 (42) in lung epithelium leads to marked induction of several elastin- and collagen-degrading MMPs and an emphysematous phenotype. In the conditional interleukin-13 transgenic, this airspace enlargement is largely abrogated in the context of the MMP-9 or -12 knockout mice (43).

The study by Zhe and colleagues in the April issue demonstrates that TIMP-3 expression is downregulated by SRF, and that LAM cells, unlike the surrounding parenchyma, express little or no TIMP-3 (7). This is particularly relevant considering that the TIMP-3 knockout mouse develops spontaneous airspace enlargement, with decreased lung collagen and impaired gas exchange (44). Also consistent with the dysregulated growth of smooth muscle–like cells in LAM, TIMP-3 is unique amongst the TIMPs in its ability to induce apoptosis. It has been shown to promote apoptosis of rat vascular smooth muscle cells (45) as well as cancer cells (46, 47), possibly by preventing the shedding of tumor necrosis factor-{alpha} receptors on these cells (47). Taken together, many of the MMPs and TIMPs which have been shown to contribute to airspace enlargement in other diseases/models are also appropriately induced or repressed in LAM, strongly suggesting that they contribute to the progressive cystic pathology in LAM as well.


   A Putative Link Between Tuberin and SRF
Top
 Introduction
 Tuberin-A Multifunctional...
 Relevance of MMPs and...
 A Putative Link Between...
References
 
SRF, which appears to repress TIMP-3 expression in LAM cells, regulates both growth factor–responsive immediate early genes, and genes expressed in skeletal, smooth, and cardiac muscle (48–50). SRF is a key transcription factor in smooth muscle cell differentiation, and regulates the expression of smooth muscle–specific differential marker genes including SM {alpha}-actin, SM myosin heavy chain, SM22, caldesmon, calponin, and telokin (51). Little is known about the origin of smooth muscle–like cells in LAM and the molecular mechanisms leading to their smooth muscle–like phenotype. The findings by Zhe and colleagues demonstrate that SRF is highly expressed in LAM cells and suggest a potential role for SRF in smooth-muscle differentiation of LAM cells. Importantly, they demonstrate the predominantly nuclear localization of SRF, which is related to the transcriptional activation of SRF in LAM cells. Activity of SRF is regulated by Rho GTPases (52). Activated Rho is sufficient to activate SRF in the absence of extracellular stimuli, and functional Rho is required for SRF activation by lysophosphatidic acid or serum (52). The importance of Rho-dependent nuclear localization for SRF activation has been demonstrated in airway myocytes (53, 54).

Because the pathology of LAM is associated with TSC2 mutations, an outstanding question concerns how loss of tuberin function may be linked to the regulation of SRF activity and gene expression. The potential link may be the fact that tuberin acts as a molecular chaperone (15) and forms a cytosolic heteromer with hamartin, which is encoded by the tumor suppressor gene TSC1 (55), and which regulates Rho GTPase activation (56). The cellular functions of tuberin and hamartin are interlinked, because mutations in either TSC1 or TSC2 genes cause tumors with similar phenotype in TS disease (3). Hamartin regulates the activity of Rho GTPase and associates with the cortical proteins ezrin/radixin/moezin, which serve as molecular bridges between the plasma membrane and the cortical actin filaments (56). As seen in Figure 2, we may speculate that dysregulation of tuberin function due to TSC2 loss or mutation may result in the disruption of the normal tuberin–hamartin interaction, which results in Rho activation, followed by SRF-dependent gene transcription. The fact that the Rho-activating domain of hamartin overlaps with the binding domain for tuberin further suggests the importance of the tuberin–hamartin interaction for their functions. The biochemistry and structure-functional characterization of the separate functions of tuberin and hamartin and the tuberin–hamartin complex is essential for the advancement our knowledge of LAM and TS. Further investigation will be required to define the linkage that likely exists between tuberin and SRF.



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  		Figure 2. Potential model of cross-talk between tuberin signaling, SRF activation, and TIMP-3 expression. Dysregulation of tuberin function due to TSC2 loss or mutation disrupts the interaction of tuberin and hamartin and promotes hamartin-dependent activation of Rho GTPase, which results in the translocation of SRF to the nucleus where it effects repression of TIMP-3.

 

   Acknowledgments
 
This work was supported in part by grants from National Heart, Lung, and Blood Institute RO1 HL071106-01 (V.P.K.), RO1 HL67353-02 (J.M.S.), RO1 HL60647-05 (J.M.S.), the LAM Foundation (J.M.S. and V.P.K.), the Barnes-Jewish Hospital Foundation (J.M.S.), and University of Pennsylvania Research Fund (V.P.K.).


   Footnotes
 
The article to which this Perspective refers was published in the April 2003 issue.

* J. Michael Shipley, Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, Box 8052, 216 S. Kingshighway Blvd., St. Louis, MO 63110. E-mail: shipleym{at}msnotes.wustl.edu Back

Received in original form March 18, 2003


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