Amino Acid Transporters: Roles for Nutrition and Signalling in Embryonic and Induced Pluripotent Stem Cells


Amino acids serve both to nourish and signal in cells and, consequently, so do their biomembrane transporters. In fact, some of these transporters may initiate signalling while transporting an amino acid substrate rather than serving simply to transport a signalling molecule. Most amino acid transporters now appear to have been cloned, and virtually all of the cloned transporters are listed in solute carrier tables for easy access online ( It is more difficult to decide as to which transporters are expressed in a given tissue, and their transport and signalling functions will likely continue to emerge long after all of the transporters have been identified. These ongoing investigations of transporter identification and function for embryonic and induced pluripotent stem cells are illustrated. Surprisingly, characterisation of amino acid transport in these cells is in its infancy. Thus, they serve as an experimental model for investigating the expression of known and novel transporters.

Key Concepts:

  • At least 55 genes encode amino acid transporters in a minimum of 10 gene families (see tables at

  • An amino acid may be listed as a substrate for a cloned transporter in these tables even though its transport has not been studied in detail.

  • The characteristics of cloned amino acid transporters may not correspond to the ways they function in cellular physiology.

  • Stem cells serve as an experimental model for investigating the expression of known and novel transporters.

  • Threonine uptake and glutamate exodus from stem cells via transporters each fosters cellular proliferation.

  • Glutamate exodus from stem cells is needed to stimulate glutamate receptors.

  • Proline uptake by stem cells promotes their differentiation.

  • mTOR signalling in stem cells is necessary for both proline‐induced differentiation and threonine‐induced proliferation.

  • Both threonine and glutamate promote stem cell proliferation by enhancing the expression of cMyc.

  • Threonine and glutamate likely foster proliferation in human as well as mouse stem cells.

Keywords: amino acid transport systems; amino acid signalling; blastocyst inner cell mass; embryonic stem cells; induced pluripotent stem cells

Figure 1.

One‐cell embryos that do not express the slc7a2 product (CAT2 knockout embryos) have reduced system b+1 activity relative to one‐cell embryos from genetically similar control mice. CAT2 knockout mice (and embryos) do not express a functional CAT2 protein (slc7a2 product). System b+1 activity was measured as defined previously (Van Winkle, ). The mean (±S.E.) activities shown were each calculated from 6 to 13 determinations obtained in 3–6 independent experiments. The total system b+1 activity in one‐cell embryos from CAT2 knockout mice was significantly lower than the activity in embryos from otherwise genetically similar control mice as determined in a group comparison t‐test (p<0.01). The reduction in activity is attributed to the lack of functional CAT2 expression, whereas the activity remaining in one‐cell embryos from CAT2 knockout mice is attributed to CAT1 (slc7a1 product) and, possibly, CAT3 (slc7a3 product) expression (Table ). CAT1, CAT2 and probably CAT3 normally are expressed throughout preimplantation development. The lack of reduction in system b1+ activity in CAT2 knockout two‐cell conceptuses is attributed to an increased expression of CAT1 or CAT3 upon activation of the embryo genome at the late one‐cell stage to compensate for the missing CAT2 activity. See text for further discussion.

Figure 2.

Changes in the aspartate (Asp), glutamate (Glu) and glutamine (Gln) content of preimplantation mouse embryos during development in vivo. Stages of development at various times after fertilisation are 35 h=2‐cell, 59 h=4‐ to 8‐cell, 83 h=earlier blastocyst and 107 h=later blastocyst.

Data from Tables 2 and 5 of Van Winkle and Dickinson .
Figure 3. Weak inhibition of [3H] Pro uptake by l‐Thr and MeAIB.
Figure 4. Partial inhibition of [3H] Pro uptake by l‐Thr and MeAIB.


Cappuccio I, Spinsanti P, Porcellini A et al. (2005) Endogenous activation of mGlu5 metabotropic glutamate receptors supports self‐renewal of cultured mouse embryonic stem cells. Neuropharmacology 49: 196–205.

Hatanaka T, Huang W, Wang H et al. (2000) Primary structure, functional characteristics and tissue expression pattern of human ATA2, a subtype of amino acid transport system A. Biochimica et Biophysica Acta 1467: 1–6.

Hediger MA, Clemencon B, Burrier RE and Bruford EA (2013) The ABC's of membrane transporters in health and disease (SLC series): introduction. Molecular Aspects of Medicine 34: 95–107.

Hediger MA, Romero MF, Peng J‐B et al. (2004) The ABC's of solute carriers: physiological, pathophysiological and therapeutic implications of human membrane transport proteins. Pflugers Archiv – European Journal of Physiology 447: 465–468.

Idris Anas MA, Hammer MA, Lever M, Stanton JA and Baltz JM (2007) The organic osmolytes betaine and proline are transported by a shared system in early preimplantation mouse embryos. Journal of Cellular Physiology 210: 266–277.

Martin PM, Sutherland AE and Van Winkle LJ (2003) Amino acid transport regulates blastocyst implantation. Biology of Reproduction 69: 1101–1108.

Ryu JM and Han HJ (2011) l‐Threonine regulates G1/S phase transition of mouse embryonic stem cells via P13K/Akt, MAPKs, and mTORC pathways. Journal of Biological Chemistry 286: 23667–23678.

Sobczak I and Lolkema JS (2005) Structural and mechanistic diversity of secondary transporters. Current Opinion in Microbiology 8: 161–167.

Spinsanti P, De Vita T, Di Castro S et al. (2006) Endogenously activated mGlu5 metabotropic glutamate receptors sustain the increase in c‐Myc expression induced by leukaemia inhibitory factor in cultured mouse embryonic stem cells. Journal of Neurochemistry 99: 299–307.

Tan BSN, Lonic A, Morris MB, Rathjen PD and Rathjen J (2011) The amino acid transporter SNAT2 mediates l‐proline‐induced differentiation of ES cells. American Journal of Physiology 300: C1270–C1279.

Van Winkle LJ (1999) Biomembrane Transport. San Diego, CA: Academic Press.

Van Winkle LJ (2001) Amino acid transport regulation and early embryo development. Biology of Reproduction 64: 1–12.

Van Winkle LJ, Campione AL, Galat S et al. (2011) Human embryonic stem cells depend on threonine for proliferation as mouse embryonic stem cells do. Biology of Reproduction 85 (abstract).

Van Winkle LJ and Dickinson HR (1995) Differences in amino acid content of preimplantation mouse embryos that develop in vitro versus in vivo: in vitro effects or five amino acids that are abundant in oviductal secretions. Biology of Reproduction 52: 96–104.

Van Winkle LJ, Tesch JK, Shah A and Campione AL (2006) System Bo,+ amino acid transport regulates the penetration stage of blastocyst implantation with possible long‐term development consequences through adulthood. Human Reproduction Update 12: 145–157.

Wang J, Alexander P, Wu L et al. (2009) Dependence of mouse embryonic stem cells on threonine catabolism. Science 325: 435–439.

Washington JM, Rathjen J, Felquer F et al. (2009) l‐Proline induces differentiation of ES cells: a novel role for an amino acid in the regulation of pluripotent cells in culture. American Journal of Physiology 298: C982–C992.

Further Reading

Bilic J and Izpisua Belmonte JC (2012) Concise review: Induced pluripotent stem cells versus embryonic stem cells: close enough or yet too far apart? Stem Cells 30: 33–41.

Bröer S (2008) Amino acid transport across mammalian intestinal and renal epithelia. Physiological Reviews 88: 249–286.

Bröer S and Palacín M (2011) The role of amino acid transporters in inherited and acquired diseases. Biochemical Journal 436: 193–211.

Hindley C and Philpott A (2013) The cell cycle and pluripotency. Biochemical Journal 451: 135–143.

Puri MC and Nagy A (2012) Concise review: embryonic stem cells versus induced pluripotent stem cells: the game is on. Stem Cells 30: 10–14.

Sommer CA and Mostoslavsky G (2013) The evolving field of induced pluripotency: recent progress and future challenges. Journal of Cellular Physiology 228: 267–275.

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Van Winkle, Lon J(Sep 2013) Amino Acid Transporters: Roles for Nutrition and Signalling in Embryonic and Induced Pluripotent Stem Cells. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000011.pub3]